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General Principles of Antimicrobial Therapy:
Antibiotics are antibacterial substances produced by various species of microorganisms(bacteria, fungi, and actinomycetes) that suppress the growth of other microorganisms. Common usage often extends the term antibiotics to include synthetic antimicrobial agents, such as sulfonamides and quinolones
Mechanism of Action
Antimicrobial agents are classified based on chemical structure and proposed mechanism of action, as follows:
(1) agents that inhibit synthesis of bacterial cell walls, including the -lactam class (e.g., penicillins, cephalosporins, and carbapenems) and dissimilar agents such as cycloserine, vancomycin, and bacitracin;
2) agents that act directly on the cell membrane of the microorganism, increasing permeability and leading to leakage of intracellular compounds, including detergents such as polymyxin; polyene antifungal agents (e.g., nystatin and amphotericin B) which bind to cell-wall sterols; and the lipopeptide daptomycin .
(3) agents that disrupt function
of 30S or 50S ribosomal subunits to reversibly inhibit protein synthesis, which generally are bacteriostatic (e.g., chloramphenicol, the tetracyclines, erythromycin, clindamycin, streptogramins, and linezolid);
(4) agents that bind to the 30S ribosomal subunit and alter protein synthesis, which generally are bactericidal (e.g., the aminoglycosides);
(5) agents that affect bacterial nucleic acid metabolism, such as the rifamycins (e.g., rifampin and rifabutin), which inhibit RNA polymerase, and the quinolones, which inhibit topoisomerases
(6) the antimetabolites, including trimethoprim and the sulfonamides, which block essential enzymes of folate metabolism.
There are several classes of antiviral agents, including:
(1) nucleic acid analogs, such as acyclovir or ganciclovir, which selectively inhibit viral DNA polymerase, and zidovudine or lamivudine, which inhibit HIV reverse transcriptase;
(2) non-nucleoside HIV reverse transcriptase inhibitors, such as nevirapine or efavirenz;
(3) inhibitors of other essential viral enzymes, e.g., inhibitors of HIV protease or influenza neuraminidase;
(4) fusion inhibitors such as enfuvirtide.
Resistance:
For an antibiotic to be effective, it must reach its target in an active form, bind to the target, and interfere with its function. Accordingly, bacterial resistance to an antimicrobial agent is attributable to three general mechanisms:
(1) The drug does not reach its target,
(2) the drug is not active,
(3) the target is altered ( The outer membrane of gram-negative bacteria is a permeable barrier that excludes large polar molecules from entering the cell.
Small polar molecules, including many antibiotics, enter the cell through protein channels called porins. Absence of, mutation in, or loss of a favored porin channel can slow the rate of drug entry into a cell or prevent entry altogether, effectively reducing drug concentration at the target site. If the target is intracellular and the drug requires active transport across the cell membrane, a mutation or phenotypic
change that shuts down this transport mechanism can confer resistance. For example, gentamicin, which targets the ribosome, is actively transported across the cell membrane using energy provided by the membrane electrochemical gradient. This gradient is generated by respiratory enzymes that couple electron transport and oxidative phosphorylation.
A mutation in an enzyme in this pathway or anaerobic conditions (oxygen is the terminal electron acceptor of this pathway, and its absence reduces the membrane potential energy) slows entry of gentamicin into the cell, resulting in resistance. Bacteria also have efflux pumps that can transport drugs out of the cell. Resistance to numerous drugs, including tetracycline, chloramphenicol, fluoroquinolones, macrolides, and -lactam antibiotics, is mediated by an efflux pump mechanism
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