Summary
10.1 Fundamentals of Antimicrobial Chemotherapy
- 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, when narrow-spectrum antimicrobials fail, or for the treatment or prevention of infections with multiple types of microbes.
10.2 Mechanisms of 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 subunit (aminoglycosides and tetracyclines) and others that bind to the 50S subunit (macrolides, lincosamides, chloramphenicol, and oxazolidinones).
- Polymyxins are lipophilic polypeptide antibiotics that target the lipopolysaccharide component of gram- negative bacteria and ultimately disrupt the integrity of the outer and inner membranes of these bacteria.
- The nucleic acid synthesis inhibitors rifamycins and fluoroquinolones target bacterial RNA transcription and DNA replication, respectively.
- Some antibacterial drugs are antimetabolites, acting as competitive inhibitors for bacterial metabolic enzymes. Sulfonamides and trimethoprim are antimetabolites that interfere with bacterial folic acid synthesis.
10.3 Mechanisms of Other Antimicrobial Drugs
- 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.
- Antifungal drugs interfere with ergosterol synthesis, bind to ergosterol to disrupt fungal cell membrane integrity, or target cell wall-specific components or other cellular proteins.
- Antiprotozoan drugs increase cellular levels of reactive oxygen species, interfere with protozoal DNA replication (nuclear versus kDNA, respectively), and disrupt heme detoxification.
- Antihelminthic drugs disrupt helminthic and protozoan microtubule formation; block neuronal transmissions; inhibit anaerobic ATP formation and/or oxidative phosphorylation; induce a calcium influx in tapeworms, leading to spasms and paralysis; and interfere with RNA synthesis in schistosomes.
- Antiviral drugs inhibit viral entry, inhibit viral uncoating, inhibit nucleic acid biosynthesis, prevent viral escape from endosomes in host cells, and prevent viral release from infected cells.
- Because it can easily mutate to become drug resistant, HIV is typically treated with a combination of several antiretroviral drugs, which may include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and drugs that interfere with viral binding and fusion to initiate infection.
10.4 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.
- Common modes of antimicrobial drug resistance include drug modification or inactivation, prevention of cellular uptake or efflux, target modification, target overproduction or enzymatic bypass, and target mimicry.
- Problematic microbial strains showing extensive antimicrobial resistance are emerging; many of these strains can reside as members of the normal microbiota in individuals but also can cause opportunistic infection. The transmission of many of these highly resistant microbial strains often occurs in clinical settings, but can also be community-acquired.
10.5 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.
- There are several laboratory methods available for determining the minimum inhibitory concentration (MIC) of an antimicrobial drug against a specific microbe. The minimal bactericidal concentration (MBC) can also be determined, typically as a follow-up experiment to MIC determination using the tube dilution method.
10.6 Current Strategies for Antimicrobial Discovery
- Current research into the development of antimicrobial drugs involves the use of high-throughput screening and combinatorial chemistry technologies.
- New technologies are being developed to discover novel antibiotics from soil microorganisms that cannot be cultured by standard laboratory methods.
- Additional strategies include searching for antibiotics from sources other than soil, identifying new antibacterial targets, using combinatorial chemistry to develop novel drugs, developing drugs that inhibit resistance mechanisms, and developing drugs that target virulence factors and hold infections in check.
