Microbiology Topic 5: Antimicrobial drugs

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History and properties of antimicrobial agents

Chemotherapy originated with Paul Ehrlich. Ehrlich originated the concept of selective toxicity. Ehrlich and Sahachiro Hata discovered the effectiveness of arsphenamine (salvarsan) against the syphilis spirochete.

Alexander Fleming

Serendipitous discovery of Penicillin, began era of antibiotics. Penicillium mold produces a substance that kills gram-positive bacteria.

Important properties of antimicrobial agents

Synthetic agents are made in a pharmaceutical lab. Antibiotics are products of or derived from living microorganisms. Semisynthetic drugs include synthetic and antibiotic elements: Improve the efficacy of the natural product; reduce its side effects; Circumvent developing resistance by targeted bacteria; expand the range of bacteria that can be treated with it.

Selective toxicity

Means that a drug should harm the pathogen but not the host. The toxic dose of a drug is the concentration causing harm to the host. The therapeutic dose is the concentration eliminating pathogens in the host. Together, the toxic and therapeutic doses are used to formulate the chemotherapeutic index.

Antimicrobial spectrum

Broad spectrum drugs affect many taxonomic groups. Narrow spectrum drugs affect only a few pathogens.

Synthetic antibacterial agents

Sulfanilamide and other sulfonamides target specific metabolic reactions. Sulfonamides out compete essential folic acid components for binding sites in a bacterial enzyme. They prevent nucleic acid synthesis and DNA replication.

Isoniazid

Synthetic antimicrobial. Interferes with cell wall synthesis in species of mycobacterium.

Quinolones

Synthetic antimicrobial. Block DNA synthesis in bacteria. Dervitives are called fluoroquinolones and are used to treat urinary tract infections. Ex. Ciprofloxacin.

The beta-lactam family of antibiotics

Penicillin has remained the most widely used antibiotic. They are active against many gram-positive and some gram-negative bacteria. They interfere with cell wall synthesis, causing the cell to burst. Some individuals experience anaphylactic allergic reaction. Many penicillin-resistant species produce beta-lactamases (penicillinase) that inactivate penicillin. Numerous semisynthetic penicillins have been developed (Ampicillan, Amoxicillin, Carbenicillin)

Cephalosporins

Beta-lactam antibiotic. Broader spectram alternatives to penicillins.

Monobactams

Beta-lactam antibiotic. Active against aerobic, gram-negative rods.

Carbapenems

Beta-lactam antibiotic. Broader spectrum drugs. ex: Imipenem.

Vancomycin

Inhibits cell wall synthesis. Effective against gram-positive bacteria such as staphylococci. Side effects include damage to ears and kidneys.

Bacitracin

Polypeptide antibiotic. Interferes with transport of cell wall precursors through the membrane. It is toxic internally, so is used topically.

Polymyxins

Poly peptide antibiotic. Increases membrane permeability of gram-negative rods. Neomycin, polymyxin B.

Aminoglycosides

Attach to bacterial ribosomes, blocking translation of RNA into proteins. Streptomycin is sometimes used in tuberculosis cases. Gentamicin is used against gram-negative infections in the urinary tract. Neomycin is used for intestinal infections and as an ointment. Kanamycin is used against gram-negative bacteria wound tissue.

Chloramphenicol

used against a wide variety of bacteria and some rickettsiae and fungi. It is reserved for serious infections like: meningitis, cholera, typhoid and typhus fevers, Rocky mountain spotted fever. Severe side effects include aplastic anemia and gray syndrome.

Tetracyclines

have a similar antimicrobial range to chloramphenicol (Doxycycline). Broad spectrum antibiotic. Interferes with protein synthesis. They can destroy intestinal microbiota and cause staining of the teeth.

Erythromycin

Macrolide used against gram-positive bacteria.

Clindamycin

a semisynthetic drug used against penicillin-resistant bacteria-Pseudomembranous colitis can occur if microbiota are killed, allowing Clostridium difficile to flourish.

Streptogramins

effective against gram-positive bacteria.

Oxazolidinones

Effective against gram-positive bacteria, including multidrug-resistant Staphylococcus aureus.

Rifampin

Interferes with RNA synthesis. It is effective against tuberculosis, leprosy, and meningitis. Can cause liver damage.

Antibiotic assays and resistance

The tube dilution method determines the minimum inhibitory concentration (MIC). The agar disk diffusion method involves different antibiotics diffusing from paper disks in a bacterial colony.

Four mechanisms of antibiotic resistance

1) Antibiotic inactivation- bacteria may evolve the ability to enzymatically inactivate an antibiotic. 2) Target modification- bacteria can evolve changes in drug targets like ribosomes or enzymes involved in replication. 3) Active export of antibiotics- Bacteria may evolve the ability to prevent drug entry into the cytoplasm or to pump the drug out of the cytoplasm. 4) Alternate metabolic pathway- Resistance to sulfonamides may develop if the bacterial enzyme changes or if the bacteria evolves an alternate metabolic pathway.

Misuse of antibiotics

Unnecessarily large antibiotic doses allow resistant strains to overgrow susceptible ones. If resistant strains spread to other patients, a superinfection occurs. Drug companies promote antibiotics, patients pressure doctors for quick cures, doctors prescribe instead of running costly tests, patients don't finish antibiotics. Antibiotics are available over the counter in developing countries, allowing for overuse and incorrect use. Antibiotic use is widespread in livestock feeds; they can be transmitted to humans through meat consumption. Bacterial cells can pass resistance genes to other bacterial cells.

New approaches to antibiotic therapy needed

Scientists work to find new antibiotic targets in pathogens; The lipopolysaccharide in gram-negative membranes contains several possible targets. Discovery of new and unique antibiotics is necessary. Use of bacteriophages (viruses that kill bacteria). Public and physician education.

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