- 17.1: Discovering Antimicrobial Drugs
- Antimicrobial drugs produced by purposeful fermentation and/or contained in plants have been used as traditional medicines in many cultures for millennia. The purposeful and systematic search for a chemical “magic bullet” that specifically target infectious microbes was initiated by Paul Ehrlich in the early 20th century. The discovery of the natural antibiotic, penicillin, by Alexander Fleming in 1928 started the modern age of antimicrobial discovery and research.
- 17.2: Properties of Antimicrobial Drugs
- Antimicrobial drugs can be bacteriostatic or bactericidal, and these characteristics are important considerations when selecting the most appropriate drug. The use of narrow-spectrum antimicrobial drugs is preferred in many cases to avoid superinfection and the development of antimicrobial resistance. Broad-spectrum antimicrobial use is warranted for serious systemic infections when there is no time to determine the causative agent or when narrow-spectrum antimicrobials fail.
- 17.3: Antibacterial Drugs
- Antibacterial compounds exhibit selective toxicity, largely due to differences between prokaryotic and eukaryotic cell structure. Cell wall synthesis inhibitors, including the β-lactams, the glycopeptides, and bacitracin, interfere with peptidoglycan synthesis, making bacterial cells more prone to osmotic lysis. There are a variety of broad-spectrum, bacterial protein synthesis inhibitors that selectively target the prokaryotic 70S ribosome, including those that bind to the 30S and 50S subunits.
- 17.4: Drugs Targeting Other Microorganisms
- Because fungi, protozoans, and helminths are eukaryotic organisms like human cells, it is more challenging to develop antimicrobial drugs that specifically target them. Similarly, it is hard to target viruses because human viruses replicate inside of human cells.
- 17.5: The Emergence of Drug Resistance
- Antimicrobial resistance is on the rise and is the result of selection of drug-resistant strains in clinical environments, the overuse and misuse of antibacterials, the use of subtherapeutic doses of antibacterial drugs, and poor patient compliance with antibacterial drug therapies. Drug resistance genes are often carried on plasmids or in transposons that can undergo vertical transfer easily and between microbes through horizontal gene transfer.
- 17.6: Testing the Effectiveness of Antimicrobials
- The Kirby-Bauer disk diffusion test helps determine the susceptibility of a microorganism to various antimicrobial drugs. However, the zones of inhibition measured must be correlated to known standards to determine susceptibility and resistance, and do not provide information on bactericidal versus bacteriostatic activity, or allow for direct comparison of drug potencies. Antibiograms are useful for monitoring local trends in antimicrobial resistance/susceptibility.
- 17.7: Antimicrobial Drugs (Exercises)
Thumbnail: Staphylococcus aureus - Antibiotics Test plate. Image used with permission (Public Domain; CDC / Provider: Don Stalons).
List of 8 Important Antibacterial Drugs | Drugs | Pharmacology
List of eight important antibacterial drugs:- 1. Sulfonamides 2. Trimethoprim 3. Co-Trimoxazole 4. Nitrofurantoin 5. Methenamine 6. Metronidazole 7. Quinolones 8. Fluoroquinolones.
Antibacterial Drug # 1. Sulfonamides:
Sulfonamides are rarely used, because of increasing bacterial resistance. They have been replaced by antibiotics, which are generally more potent and less toxic.
Sulfonamides are bacteriostatic. They, being structural analogues of para-amino benzoic acid (PABA), are taken up by bacteria instead of PABA (competitive inhibition) and prevent bacterial folic acid synthesis, which is necessary for their multiplication. Susceptible bacteria are those, which need PABA, because they are incapable of using folic acid directly. Human cells use exogenous folic acid and thus, a lack of PABA does not affect them.
Sulfonamides, with exceptions, are readily absorbed following oral administration. They are widely distributed into body fluids and cross blood brain barrier to enter cerebrospinal fluid. They are metabolized by acetylation in the liver, which negates the antibacterial activity, but not the adverse effects. The acetylated fraction is very poorly soluble and tends to precipitate in the urine, unless an adequate flow in maintained.
Sulfonamides are effective against a fairly wide range of bacteria, which includes gram-positive bacteria and some gram-negative bacteria such as E. coli (the organism responsible for acute urinary tract infection), Haemophilus influenza and Shigella. Other susceptible organisms include B. anthrax, Nocardia, Toxoplasma.
Sulfonamides are rarely used in urinary tract infections and chronic bronchitis, provided the causative organisms are susceptible and for the prophylaxis of rheumatic fever. Sulfadimidine (1 g every 6 hours) or long acting sulfametopyrazine (2 g once weekly) are the preferred sulfonamides. Silver sulfadiazine is applied locally as a cream to prevent infections in burns. Sulfasalazine is used for ulcerative colitis, Crohn’s disease and rheumatoid arthritis.
Severe side effects of sulfonamides are rashes, Stevens-Johnson syndrome, renal failure, bone marrow depression and agranulocytosis. Sulfonamides are contraindicated in hepatic or renal failure and in porphyria.
Antibacterial Drug # 2. Trimethoprim:
Trimethoprim is chemically related to the antimalarial drug pyrimethamine. It is bacteriostatic in action and acts by interfering with folic acid metabolism at the phase when folic acid is converted to folinic acid to build up the cell nucleus. Trimethoprim selectively inhibits the enzyme dihydrofolate reductase which converts the folic acid to folinic acid resulting in the death of the bacterial cell. The pharmacological aspects of trimethoprim are very similar to sulfonamides. Trimethoprim can be used alone for urinary and respiratory infections, prostatitis, shigellosis and invasive salmonella infection.
Antibacterial Drug # 3. Co-Trimoxazole:
It is a combination of a sulfonamide (sulfamethoxazole) and trimethoprim in the proportion of 5 parts to 1 part and is bactericidal because of their synergistic activity. It has excellent tissue penetration, including bone, prostate and brain. Co-trimoxazole is the drug of choice in Pneumocystis crainii and Nocardia infection. It can also be used in acute exacerbation of chronic bronchitis, urinary tract infections and acute otitis media in children, provided the causative organism is susceptible. It is given in doses of500 mg twice daily. Side effects are essentially that of sulfonamides.
Antibacterial Drug # 4. Nitrofurantoin:
Nitrofurantoin has a fairly wide antibacterial spectrum against gram-negative bacteria responsible for urinary tract infections. It is well absorbed and is considerably concentrated in the urine. It is bactericidal and is used in uncomplicated lower urinary tract infections (especially in vancomycin-resistant Enterococcus faeciumi) except those caused by Proteus and P. aeruginosa. Prolonged therapy with nitro-furantoin should be avoided, as it is associated with chronic pulmonary syndromes that can be fatal. Nausea is the most common adverse effect and others include rashes, fever and blood disorders. It should not be used in impaired renal function, as accumulation will occur.
Antibacterial Drug # 5. Methenamine:
Methenamine is a urine/bladder antiseptic that is converted to formaldehyde in the urine when the pH is less than 6.0. It is rarely used because of the large number of antibiotics that are available. However, it has a limited role in uncomplicated UTI caused by multiple drug-resistant bacteria or yeast. Side effects include bladder irritation, dysuria, and hematuria with prolonged use. It is contraindicated in glaucoma, renal insufficiency, and acidosis and should not be used concomitantly with sulfonamides.
Antibacterial Drug # 6. Metronidazole:
Metronidazole (500 mg orally or by IV infusion every 8 hours) is one of the most important antimicrobial drug and is extensively used in diverse clinical conditions. It kills anaerobic bacteria and some protozoa.
Metronidazole is well absorbed orally (bioavailability 90%) and is widely distributed in the body tissues, attaining therapeutic concentrations in vaginal secretions, semen, saliva, breast milk and CNS. It penetrates into bone and abscess cavities. More than 50% of the drug is metabolized in the liver.
Metronidazole is highly effective against anaerobic bacteria and protozoa. It has greater activity against gram-negative than gram- positive anaerobes but is active against Clostridium perfringens (causative organism for gas gangrene, colitis and food poisoning) and C. difficile (causes pseudomembranous colitis). Protozoa that respond to metronidazole include Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis. It has no direct effect on helminth Dracunculus medinensis, but helps in the elimination of guineaworm.
Metronidazole is one of the most widely used drugs in diverse clinical disorders, which includes
Acute invasive intestinal amoebic dysentery and extra­-intestinal amoebiasis including amoebic liver and brain abscess (800 mg 6 hourly/ 5-10 days). Urogenital trichomoniasis (2 g as a single dose or 200 mg 8 hourly/ 7 days). Giardiasis (2 g daily/ 3 days).
Metronidazole is highly effective against anaerobic infections in:
a. Leg ulcers and pressure sores
c. Acute ulcerative gingivitis
d. Acute dental infections
e. Antibiotic associated colitis (pseuomembranous colitis)
Intra-abdominal infections and brain abscess (usually in combination with a cephalosporin). Surgical and gynecological sepsis in which its activity against colonic anaerobes, especially B. fragilis is important. Intravenous (500 mg every 8 hours) metronidazole together with human tetanus immunoglobulin in established cases of tetanus.
H. pylori eradication along with omeprazole (proton pump inhibitor) and clarithromycin.Topical metronidazole gel 0.75% in the management of acne rosacea and for reduction of the odour produced by anaerobic bacteria in fungating tumours.
Metronidazole may cause GIT disturbances. Rarely, it may cause neurological and blood disorders and anaphylaxis. With alcohol, it produces disulfiram like reactions.
Antibacterial Drug # 7. Quinolones:
Nalidixic acid was the first quinolone to be introduced in 1960 for the treatment of GIT and urinary infections, but bacterial resistance and side effects limited its use. The development of fluorinated derivatives called fluoro­quinolones resulted in antibacterial activity with extended spectrum, higher potency, better tissue penetration and lesser bacterial resistance.
Antibacterial Drug # 8. Fluoroquinolones:
Fluoroquinolones are rapidly bactericidal. They interfere with an enzyme (DNA gyrase) which is necessary for the cell division (DNA replication) of bacteria.
Fluoroquinolones have a wide range of antibacterial activity. They are active against both gram- positive and gram-negative bacteria. They are particularly active against gram-negative bacteria, including Salmonella, Shigella, Campylobacter, Neisseria and Pseudomonas. They are moderately active against gram-positive bacteria such as Strep, pneumonia and Enterococcus fecalis, Chlamydia, Mycoplasma and some Mycobacteria. Most anaerobic organisms are not susceptible.
Fluoroquinolones are well absorbed orally. The maximum serum levels are similar irrespective of the route (oral or IV) of administration. They are widely-distributed throughout the body. Concentrations in lung, sputum, muscle, bone, prostate and phagocytes exceed that in plasma. They are excreted in urine. Antacids, sucralfate, bismuth, iron, calcium and zinc preparations markedly impair oral absorption.
Norfloxacin (400 mg 12 hourly) and lomefloxacin (400 mg daily) orally are useful in urinary tract infections caused by gram-negative organisms, but are not the fluoroquinolones of choice. They are not used for systemic infections. They should not be used in children and pregnancy, in cases of porphyria and renal impairment.
Ciprofloxacin (500 mg orally once a day or 200-400 mg IV 12 hourly) and ofloxacin (200-400 mg orally or IV 12 hourly) are active against gram-negative aerobes including many ampicillin beta-lactamase-producing organisms. These drugs are commonly used for anthrax, urinary tract infections, pyelonephritis, infectious diarrhea, typhoid fever, prostatitis, gonorrhea (single-dose therapy) and intra-abdominal infections (with metronidazole). They are the preferred drugs in adults as a prophylactic for close contact with meningococcal meningitis.
Ciprofloxacin is the most active quinolone against P. aeruginosa and is the quinolone of choice for serious infections with this organism. It has relatively poor activity against gram-positive cocci and anaerobes, and should not be used as empiric mono-therapy for community-acquired pneumonia, skin and soft-tissue infections or intra-abdominal infections.
Levofloxacin (250-750 mg), gatifloxcin (400 mg), sparfloxacin (200-400 mg) and moxifloxacin (400 mg) are newer fluoroquinolones with improved coverage of aerobic gram-positive organisms (streptococci, staphylococci) and atypical respiratory pathogens (Chlamydia pneumonia, Mycoplasma, Legionella) but have less gram-negative activity (especially against P. aeruginosa) than ciprofloxacin. They can be used orally or IV, given every 12 hourly. Moxifloxacin and gatifloxacin have reasonable anaerobic activity, making them useful in mixed aerobic/anaerobic infections.
The important therapeutic uses of newer fluoroquinolones are:
a. Sinusitis, bronchitis and community acquired pneumonia
b. Urinary tract infections (except moxifloxacin, since it is minimally excreted in the urine)
c. Soft-tissue infections as an alternative to β lactum antibiotics
d. Postoperative surgical, obstetrical/gynaecological infections
e. Multidrug resistant TB and atypical mycobacterial infections
The principal adverse reactions with fluoroquinolones are gastrointestinal upsets (nausea) and skin rashes. They should be avoided, if possible, in patients with epilepsy as they have the potential to cause seizures, and in children they may cause damage to developing weight-bearing joints. They can also cause pain and inflammation of tendons, especially in older people.
Fluoroquinolones should be discontinued if psychiatric, neurological or hypersensitivity symptoms occur. NSAIDs and theophylline increase the risk of convulsions and anticoagulant action of warfarin is enhanced, if used with fluoroquinolones.
The most common mode of action for antifungal drugs is the disruption of the cell membrane. Antifungals take advantage of small differences between fungi and humans in the biochemical pathways that synthesize sterols. The sterols are important in maintaining proper membrane fluidity and, hence, proper function of the cell membrane. For most fungi, the predominant membrane sterol is ergosterol. Because human cell membranes use cholesterol, instead of ergosterol, antifungal drugs that target ergosterol synthesis are selectively toxic (Figure 1).Figure 1. The predominant sterol found in human cells is cholesterol, whereas the predominant sterol found in fungi is ergosterol, making ergosterol a good target for antifungal drug development.
The imidazoles are synthetic fungicides that disrupt ergosterol biosynthesis they are commonly used in medical applications and also in agriculture to keep seeds and harvested crops from molding. Examples include miconazole, ketoconazole, and clotrimazole, which are used to treat fungal skin infections such as ringworm, specifically tinea pedis (athlete’s foot), tinea cruris (jock itch), and tinea corporis. These infections are commonly caused by dermatophytes of the genera Trichophyton, Epidermophyton, and Microsporum. Miconazole is also used predominantly for the treatment of vaginal yeast infections caused by the fungus Candida, and ketoconazole is used for the treatment of tinea versicolor and dandruff, which both can be caused by the fungus Malassezia.
The triazole drugs, including fluconazole, also inhibit ergosterol biosynthesis. However, they can be administered orally or intravenously for the treatment of several types of systemic yeast infections, including oral thrush and cryptococcal meningitis, both of which are prevalent in patients with AIDS. The triazoles also exhibit more selective toxicity, compared with the imidazoles, and are associated with fewer side effects.
The allylamines, a structurally different class of synthetic antifungal drugs, inhibit an earlier step in ergosterol biosynthesis. The most commonly used allylamine is terbinafine (marketed under the brand name Lamisil), which is used topically for the treatment of dermatophytic skin infections like athlete’s foot, ringworm, and jock itch. Oral treatment with terbinafine is also used for the treatment of fingernail and toenail fungus, but it can be associated with the rare side effect of hepatotoxicity.
The polyenes are a class of antifungal agents naturally produced by certain actinomycete soil bacteria and are structurally related to macrolides. These large, lipophilic molecules bind to ergosterol in fungal cytoplasmic membranes, thus creating pores. Common examples include nystatin and amphotericin B. Nystatin is typically used as a topical treatment for yeast infections of the skin, mouth, and vagina, but may also be used for intestinal fungal infections. The drug amphotericin B is used for systemic fungal infections like aspergillosis, cryptococcal meningitis, histoplasmosis, blastomycosis, and candidiasis. Amphotericin B was the only antifungal drug available for several decades, but its use is associated with some serious side effects, including nephrotoxicity (kidney toxicity).
Amphotericin B is often used in combination with flucytosine, a fluorinated pyrimidine analog that is converted by a fungal-specific enzyme into a toxic product that interferes with both DNA replication and protein synthesis in fungi. Flucytosine is also associated with hepatotoxicity (liver toxicity) and bone marrow depression.
Beyond targeting ergosterol in fungal cell membranes, there are a few antifungal drugs that target other fungal structures (Figure 2). The echinocandins, including caspofungin, are a group of naturally produced antifungal compounds that block the synthesis of β(1→3) glucan found in fungal cell walls but not found in human cells. This drug class has the nickname “penicillin for fungi.” Caspofungin is used for the treatment of aspergillosis as well as systemic yeast infections.
Although chitin is only a minor constituent of fungal cell walls, it is also absent in human cells, making it a selective target. The polyoxins and nikkomycins are naturally produced antifungals that target chitin synthesis. Polyoxins are used to control fungi for agricultural purposes, and nikkomycin Z is currently under development for use in humans to treat yeast infections and Valley fever(coccidioidomycosis), a fungal disease prevalent in the southwestern US. 1
The naturally produced antifungal griseofulvin is thought to specifically disrupt fungal cell division by interfering with microtubules involved in spindle formation during mitosis. It was one of the first antifungals, but its use is associated with hepatotoxicity. It is typically administered orally to treat various types of dermatophytic skin infections when other topical antifungal treatments are ineffective.
There are a few drugs that act as antimetabolites against fungal processes. For example, atovaquone, a representative of the naphthoquinone drug class, is a semisynthetic antimetabolite for fungal and protozoal versions of a mitochondrial cytochrome important in electron transport. Structurally, it is an analog of coenzyme Q, with which it competes for electron binding. It is particularly useful for the treatment of Pneumocystis pneumonia caused by Pneumocystis jirovecii. The antibacterial sulfamethoxazole-trimethoprim combination also acts as an antimetabolite against P. jirovecii.
Table shows the various therapeutic classes of antifungal drugs, categorized by mode of action, with examples of each.Figure 2. Antifungal drugs target several different cell structures. (credit right: modification of work by “Maya and Rike”/Wikimedia Commons)
Common Antifungal Drugs
TREATING A FUNGAL INFECTION OF THE LUNGS
Jack, a 48-year-old engineer, is HIV positive but generally healthy thanks to antiretroviral therapy (ART). However, after a particularly intense week at work, he developed a fever and a dry cough. He assumed that he just had a cold or mild flu due to overexertion and didn’t think much of it. However, after about a week, he began to experience fatigue, weight loss, and shortness of breath. He decided to visit his physician, who found that Jack had a low level of blood oxygenation. The physician ordered blood testing, a chest X-ray, and the collection of an induced sputum sample for analysis. His X-ray showed a fine cloudiness and several pneumatoceles (thin-walled pockets of air), which indicated Pneumocystis pneumonia (PCP), a type of pneumonia caused by the fungus Pneumocystis jirovecii. Jack’s physician admitted him to the hospital and prescribed Bactrim, a combination of sulfamethoxazole and trimethoprim, to be administered intravenously.
P. jirovecii is a yeast-like fungus with a life cycle similar to that of protozoans. As such, it was classified as a protozoan until the 1980s. It lives only in the lung tissue of infected persons and is transmitted from person to person, with many people exposed as children. Typically, P. jirovecii only causes pneumonia in immunocompromised individuals. Healthy people may carry the fungus in their lungs with no symptoms of disease. PCP is particularly problematic among HIV patients with compromised immune systems.
PCP is usually treated with oral or intravenous Bactrim, but atovaquone or pentamidine (another antiparasitic drug) are alternatives. If not treated, PCP can progress, leading to a collapsed lung and nearly 100% mortality. Even with antimicrobial drug therapy, PCP still is responsible for 10% of HIV-related deaths.
The cytological examination, using direct immunofluorescence assay (DFA), of a smear from Jack’s sputum sample confirmed the presence of P. jirovecii (Figure 3). Additionally, the results of Jack’s blood tests revealed that his white blood cell count had dipped, making him more susceptible to the fungus. His physician reviewed his ART regimen and made adjustments. After a few days of hospitalization, Jack was released to continue his antimicrobial therapy at home. With the adjustments to his ART therapy, Jack’s CD4 counts began to increase and he was able to go back to work.Figure 3. Microscopic examination of an induced sputum sample or bronchoaveolar lavage sample typically reveals the organism, as shown here. (credit: modification of work by the Centers for Disease Control and Prevention)
BIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial Drugs
BIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial DrugsBIOLOGY 206 OpenStax Microbiology Test Bank- Chapter 14&semi Antimicrobial Drugs
Naturally Occurring Antimicrobial Drugs: Antibiotics
An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans.
Discuss the mechanism of action for protein synthesis inhibitors used as antimicrobial drugs, and recognize various naturally occuring antimicrobial drugs
- There are mainly two classes of antimicrobial drugs: those obtained from natural sources (i.e. beta-lactam antibiotic (such as penicillins, cephalosporins) or protein synthesis inhibitors (such as aminoglycosides, macrolides, tetracyclines, chloramphenicol, polypeptides) and synthetic agents.
- A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such because the nitrogen atom is attached to the β-carbon relative to the carbonyl.
- A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.
- β-lactam: A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.
- antimicrobial: An agent that destroys microbes, inhibits their growth, or prevents or counteracts their pathogenic action.
- microorganism: An organism that is too small to be seen by the unaided eye, especially a single-celled organism, such as a bacterium.
An antimicrobial is a substance that kills or inhibits the growth of microorganisms bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes (microbiocidal) or prevent the growth of microbes (microbiostatic). Disinfectants are antimicrobial substances used on non-living objects or outside the body.
A cluster of Escherichia coli Bacteria magnified 10,000 times.: A cluster of Escherichia coli Bacteria magnified 10,000 times.
The discovery of antimicrobials, like penicillin and tetracycline, paved the way for better health for millions of people around the world. Before penicillin became a viable medical treatment in the early 1940’s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.
However, with the development of antimicrobials, microorganisms have adapted and become resistant to previous antimicrobial agents. The old antimicrobial technology was based either on poisons or heavy metals, which may not have killed the microbe completely. This allowed the microbe to survive, change, and become resistant to the poisons and/or heavy metals.
Antimicrobial nanotechnology is a recent addition to the fight against disease causing organisms. It replaces heavy metals and toxins and may someday be a viable alternative.
Infections that are acquired during a hospital visit are called “hospital acquired infections” or nosocomial infections. Similarly, when the infectious disease is picked up in the non-hospital setting it is considered “community acquired. ”
There are mainly two classes of antimicrobial drugs: those obtained from natural sources (i.e. beta-lactam) antibiotic (such as penicillins, cephalosporins) or protein synthesis inhibitors (such as aminoglycosides, macrolides, tetracyclines, chloramphenicol, polypeptides) and synthetic agents.
A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone.
A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins. While a broad interpretation of this definition could be used to describe nearly any antibiotic, in practice, it usually refers to substances that act at the ribosome level (either the ribosome itself or the translation factor), taking advantage of the major differences between prokaryotic and eukaryotic ribosome structures. Toxins such as ricin also function via protein synthesis inhibition. Ricin acts at the eukaryotic 60S.
In general, protein synthesis inhibitors work at different stages of prokaryotic mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer, and ribosomal translocation), and termination. Rifamycin inhibits prokaryotic DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit. Linezolid acts at the initiation stage probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.
Tetracyclines and Tigecycline (a glycylcycline related to tetracyclines) block the A site on the ribosome, preventing the binding of aminoacyl tRNAs. Aminoglycosides, among other potential mechanisms of action, interfere with the proofreading process, causing increased rate of error in synthesis with premature termination. Chloramphenicol blocks the peptidyl transfer step of elongation on the 50S ribosomal subunit in both bacteria and mitochondria. Macrolides (as well as inhibiting ribosomal translocation and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting peptidyl transfer. Quinupristin/dalfopristin act synergistically, with dalfopristin, enhancing the binding of quinupristin as well as inhibiting peptidyl transfer. Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide. It also causes incomplete chains to be released. Macrolides, clindamycin, and aminoglycosides (with all these three having other potential mechanisms of action as well) have evidence of inhibition of ribosomal translocation. Fusidic acid prevents the turnover of elongation factor G (EF-G) from the ribosome. Macrolides and clindamycin (both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA from the ribosome. Puromycin has a structure similar to that of the tyrosinyl aminoacyl-tRNA. Therefore, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome, causing a premature termination of polypeptide synthesis.
Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread
The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread.
Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Life cycle of the malaria…
Life cycle of the malaria parasite. Transmission of malaria occurs through a vector,…
Bacteriostatic Versus Bactericidal
Antibacterial drugs can be either bacteriostatic or bactericidal in their interactions with target bacteria. Bacteriostatic drugs cause a reversible inhibition of growth, with bacterial growth restarting after elimination of the drug. By contrast, bactericidal drugs kill their target bacteria. The decision of whether to use a bacteriostatic or bactericidal drugs depends on the type of infection and the immune status of the patient. In a patient with strong immune defenses, bacteriostatic and bactericidal drugs can be effective in achieving clinical cure. However, when a patient is immunocompromised, a bactericidal drug is essential for the successful treatment of infections. Regardless of the immune status of the patient, life-threatening infections such as acute endocarditis require the use of a bactericidal drug.
Biochemistry and Molecular Biology of Antimicrobial Drug Action
This stimulating new edition of the well-respected title Biochemistry and Molecular Biology of Antimicrobial Drug Action primarily covers medically important antimicrobial agents, but also includes some compounds not in current medical use which have been invaluable as research tools in biochemistry.
Since the previous edition, of this book, the impact of molecular biology on our understanding of the mechanisms of antimicrobial action and drug resistance has evolved significantly. This is reflected in the book’s coverage with new material covering the remarkable recent developments in unraveling the complex molecular details of drug interactions with such key targets as ribosomes and the enzymes of nucleic acid replication and microbial cell wall biosynthesis. The new addition also reviews key advances in the biochemistry and molecular biology of drug-resistant pathogens including viruses, parasitic protozoa, fungi and the much feared ‘superbugs’ such as MRSA.
Completely updated and rewritten, Biochemistry and Molecular Biology of Antimicrobial Drug Action will be of great use to medical and biological sciences students taking courses in pharmacology, molecular biology, microbiology, biochemistry and chemotherapeutics. Because of the wealth of information within the covers of this important book, all those involved in research into drug action and development, whether in the pharmaceutical industry or academia, will find Biochemistry and Molecular Biology of Antimicrobial Drug Action invaluable. It should also be on the shelves of all libraries, in university medical schools and departments of biological sciences, biochemistry and pharmacology.
From the reviews of the sixth edition:
"This sixth edition builds on the successful formula of its predecessors with an accessible small format, clear diagrams and illustrations, key antibiotic structures and an engaging explanatory text. … the great strength . is that it has managed to convey the essentials of the topic without … expanding in girth at each edition. … this book remains the first port of call for those requiring an overview of the topic or seeking a starting point for more in-depth information on an unfamiliar antimicrobial." (Jonathan H Cove, British Toxicology Society Newsletter, Winter, 2005)
Antimicrobial peptides: current status and therapeutic potential
Antimicrobial peptides (AMPs) are effector molecules of the innate immune system. A variety of AMPs have been isolated from species of all kingdoms and are classified based on their structure and amino acid motifs. AMPs have a broad antimicrobial spectrum and lyse microbial cells by interaction with biomembranes. Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cell proliferation, immune induction, wound healing, cytokine release, chemotaxis and protease-antiprotease balance. AMPs qualify as prototypes of innovative drugs that may be used as antimicrobials, anti-lipopolysaccharide drugs or modifiers of inflammation. Several strategies have been followed to identify lead candidates for drug development, to modify the peptides' structures, and to produce sufficient amounts for pre-clinical and clinical studies. This review summarises the current knowledge about the basic and applied biology of AMPs.
Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents
There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies (2) coronavirus-specific pharmacodynamics (PD) (3) PK and PD interactions between proposed combination therapies (4) pharmacology of major supportive therapies and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2 potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.
Inhibitors of Cell Wall Biosynthesis
Several different classes of antibacterials block steps in the biosynthesis of peptidoglycan, making cells more susceptible to osmotic lysis (Table). Therefore, antibacterials that target cell wall biosynthesis are bactericidal in their action. Because human cells do not make peptidoglycan, this mode of action is an excellent example of selective toxicity.
Penicillin, the first antibiotic discovered, is one of several antibacterials within a class called β-lactams. This group of compounds includes the penicillins, cephalosporins, monobactams, and carbapenems, and is characterized by the presence of a β-lactam ring found within the central structure of the drug molecule (Figure 2). The β-lactam antibacterials block the crosslinking of peptide chains during the biosynthesis of new peptidoglycan in the bacterial cell wall. They are able to block this process because the β-lactam structure is similar to the structure of the peptidoglycan subunit component that is recognized by the crosslinking transpeptidase enzyme, also known as a penicillin-binding protein (PBP). Although the β-lactam ring must remain unchanged for these drugs to retain their antibacterial activity, strategic chemical changes to the R groups have allowed for development of a wide variety of semisynthetic β-lactam drugs with increased potency, expanded spectrum of activity, and longer half-lives for better dosing, among other characteristics.
Penicillin G and penicillin V are natural antibiotics from fungi and are primarily active against gram-positive bacterial pathogens, and a few gram-negative bacterial pathogens such as Pasteurella multocida. Figure 2 summarizes the semisynthetic development of some of the penicillins. Adding an amino group (-NH2) to penicillin G created the aminopenicillins (i.e., ampicillin and amoxicillin) that have increased spectrum of activity against more gram-negative pathogens. Furthermore, the addition of a hydroxyl group (-OH) to amoxicillin increased acid stability, which allows for improved oral absorption. Methicillin is a semisynthetic penicillin that was developed to address the spread of enzymes (penicillinases) that were inactivating the other penicillins. Changing the R group of penicillin G to the more bulky dimethoxyphenyl group provided protection of the β-lactam ring from enzymatic destruction by penicillinases, giving us the first penicillinase-resistant penicillin.
Similar to the penicillins, cephalosporins contain a β-lactam ring (Figure 2) and block the transpeptidase activity of penicillin-binding proteins. However, the β-lactam ring of cephalosporins is fused to a six-member ring, rather than the five-member ring found in penicillins. This chemical difference provides cephalosporins with an increased resistance to enzymatic inactivation by β-lactamases. The drug cephalosporin C was originally isolated from the fungus Cephalosporium acremonium in the 1950s and has a similar spectrum of activity to that of penicillin against gram-positive bacteria but is active against more gram-negative bacteria than penicillin. Another important structural difference is that cephalosporin C possesses two R groups, compared with just one R group for penicillin, and this provides for greater diversity in chemical alterations and development of semisynthetic cephalosporins. The family of semisynthetic cephalosporins is much larger than the penicillins, and these drugs have been classified into generations based primarily on their spectrum of activity, increasing in spectrum from the narrow-spectrum, first-generation cephalosporins to the broad-spectrum, fourth-generation cephalosporins. A new fifth-generation cephalosporin has been developed that is active against methicillin-resistant Staphylococcus aureus (MRSA).
The carbapenems and monobactams also have a β-lactam ring as part of their core structure, and they inhibit the transpeptidase activity of penicillin-binding proteins. The only monobactam used clinically is aztreonam. It is a narrow-spectrum antibacterial with activity only against gram-negative bacteria. In contrast, the carbapenem family includes a variety of semisynthetic drugs (imipenem, meropenem, and doripenem) that provide very broad-spectrum activity against gram-positive and gram-negative bacterial pathogens.
The drug vancomycin, a member of a class of compounds called the glycopeptides, was discovered in the 1950s as a natural antibiotic from the actinomycete Amycolatopsis orientalis. Similar to the β-lactams, vancomycin inhibits cell wall biosynthesis and is bactericidal. However, in contrast to the β-lactams, the structure of vancomycin is not similar to that of cell-wall peptidoglycan subunits and does not directly inactivate penicillin-binding proteins. Rather, vancomycin is a very large, complex molecule that binds to the end of the peptide chain of cell wall precursors, creating a structural blockage that prevents the cell wall subunits from being incorporated into the growing N-acetylglucosamine and N-acetylmuramic acid (NAM-NAG) backbone of the peptidoglycan structure (transglycosylation). Vancomycin also structurally blocks transpeptidation. Vancomycin is bactericidal against gram-positive bacterial pathogens, but it is not active against gram-negative bacteria because of its inability to penetrate the protective outer membrane.
The drug bacitracin consists of a group of structurally similar peptide antibiotics originally isolated from Bacillus subtilis. Bacitracin blocks the activity of a specific cell-membrane molecule that is responsible for the movement of peptidoglycan precursors from the cytoplasm to the exterior of the cell, ultimately preventing their incorporation into the cell wall. Bacitracin is effective against a wide range of bacteria, including gram-positive organisms found on the skin, such as Staphylococcus and Streptococcus. Although it may be administered orally or intramuscularly in some circumstances, bacitracin has been shown to be nephrotoxic (damaging to the kidneys). Therefore, it is more commonly combined with neomycin and polymyxin in topical ointments such as Neosporin.Figure 2. Penicillins, cephalosporins, monobactams, and carbapenems all contain a β-lactam ring, the site of attack by inactivating β-lactamase enzymes. Although they all share the same nucleus, various penicillins differ from each other in the structure of their R groups. Chemical changes to the R groups provided increased spectrum of activity, acid stability, and resistance to β-lactamase degradation.