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Folic acid inhibiting drugs • Sulfonamides (sulfa drugs) – Early synthetic drugs – Metabolic antagonists, block folic acid biosynthetic pathway – Folic acid needed for synthesis of nucleotides • Selectively toxic: folic acid is a human vitamin – Failure to synthesize DNA bacteriostatic – Resistance common • Mutation in enzyme easy • Reduced drug uptake also occurs 1 trimethoprim • Different structure, functions in same pathway – Inhibits different enzyme – Resistance also occurs from changed cell permeability and altered enzyme • Used in combinations with sulfonamides – Bactrim: sulfamethoxazole and trimethoprim – Synergistic to the point of being bactericidal – Decreased resistance by mutation from mutation rate being the product of the two rates 2 Folic acid inhibiting combos sulfamethoxazole trimethoprim http://en.wikipedia.org/wiki/Trimethoprim 3 Pharmacokinetics and use 4 • Sulfa drug family generally administered orally – Great variation in disposition, half life – Mostly combos administered • Wide variety of pathogens including non-bacterial • Treatment of opportunistic infections found with HIV infection • Treatment of urinary tract infections • Treatment of some chronic respiratory infections Side effects of folate inhibitors • Hypersensitivities including Stevens-Johnson syndrome – Severe reaction with extensive skin damage and systemic effects • Hematological effects including anemias, agranulocytosis, thrombocytopenia 5 Polymyxins 6 Cyclic peptides of amino acids and amino butyric acid. “R” is a long hydrophobic tail. Source: Bacillus polymyxa www.cas.astate.edu/ draganjac/AndreaHausman.html Polymyxins interact with OM of Gram negatives, causing leakage of periplasmic enzymes, damage cell membrane. 7 Action of Polymyxins Polymyxins • Can be used iv with caution • Toxicity primarily nephro- and neurotoxicity – Expected to have low selective toxicity because of detergent effects on cell membranes. • Typically administered topically along with neomycin and bacitracin – Combination covers cell wall inhibition, protein synthesis inhibition, and membrane attack – Effective against Gram positives and negatives 8 Fluoroquinolones 9 • Based on older drug nalidixic acid • Became familiar to public during anthrax scares • Inhibit the action of Topoisomerases including Type 2 (includes gyrase) and Topo..ase IV – Bacterial DNA is negatively supercoiled; these enzymes introduce or remove supercoiling and are required for relieving coiling stress during DNA replication. – Inhibition results in cell death due to release of DNA w/ double strand breaks. Structure and function Fluoroquinolone nucleus: Drug traps DNAenzyme complex, releases broken DNA. Type 2 enzymes produce double strand breaks 10 Pharmacokinetics and clinical use 11 • Fluoroquinolones can all be given orally – Most can also be administered iv • Most have fairly long half-life in the body (e.g. >4 hours), good penetration into compartments • Mostly renal excretion • Active against a wide range of bacteria – Urinary tract and STDs – Tough to kill bacteria – Biowarfare agents (anthrax, plague, tularemia) Toxicity • • • • • Usual wide variety of side effects GI disturbance including C. difficile problems Hypersensitivity with rashes Some degree of neuro- and hepatotixicity Damage to cartilage in developing individuals (i.e. children). • Elevated theophylline levels! 12 Chapter 49: anti-mycobacterial agents • Mycobacterium – M. tuberculosis: cause of tuberculosis • Chronic lung disease – M. avium complex (MAC) • Environmental opportunist – M. leprae: Hansen’s disease aka leprosy 13 Challenges to treatment 14 • Chronic diseases, require long term treatment • Socio-economic groups – Homeless and poor least likely to continue therapy, breeds resistance • Combination therapy required because of developing resistance • Bacteria grow intracellularly – Drug must reach target • Uncontrolled, contagious infections in immunocompromised Selected info on drugs • Mixture of synthetic drugs and antibiotics • Orally administered as befits long term care – 6 to 9 months of treatment • Typical drugs: – Isoniazid, ethambutol, rifampicin, pyrazinamide – Include many different modes of action – Some target the unique cell wall consisting of mycolic acids covalently attached to PG 15 Antifungal drugs 16 • Fungi are eukaryotes, thus removing targets of 70S ribosomes and PG. – Major target: fungal cell membrane – Other drugs target cell wall, nuclear division, and nucleic acid synthesis • Except for superficial infections, serious disease rarely occurs in healthy individual – Systemic, serious disease in immunocompromised • Older drugs powerful, but more toxic – Amphotericin B, Nystatin, etc. Azoles, Allylamines, Tolnaftate 17 • Azoles:Fluconazole, ketoconazole, miconazole – Inhibit enzyme in ergosterol pathway, compromising cell membranes – Some oral, some topical, some iv • Dependent on absorption properties • Terbinafine: allylamine marketed as Lamisil – Concentrated in hair and nails • Various azoles, terbinafine, and tolnaftate sold for treatment of superficial infections, OTC 18