Microbial Chemotherapy

chemotherapy

selective destruction of invading organisms without harming host

selective toxicity

administering substance producing maximal toxicity to organism causing disease with minimal toxicity to host tissue

Koch's postulates

-pathogenic microorganism must be found in abundance in all organisms suffering from disease but not in healthy organisms

-pathogenic microorganism must be able to be isolated from diseased organism and grown in pure culture

-cultured pathogenic microorganism should cause disease when introduced into a healthy organism

-pathogenic microorganisms must be able to be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent

antibiotic chemotherapy

concept that substances derived from one living thing may serve to kill other living things

intrinsic drug resistance

particular microbe is resistant to a particular drug

acquired drug resistance

microbe evolves to develop resistance to a drug that previously would have killed it; can be transferred to other bacteria through transduction, transformation, and conjugation

sulfonamides

first class of effective systemic chemotherapeutics; bacteriostatic against both gram-positive and gram-negative bacteria by interfering with bacterial synthesis of folic acid from PABA

used for UTIs and other infections, pulmonary lesions synergistic with trimethoprim

sulfonamide resistance

_____ develops by increasing PABA synthesis, alterations in enzyme that uses PABA, increased capacity to destroy/inactivate drug, alternative metabolic pathways

principle of independent solubility

each sulfonamide acts independently in terms of their solubilities but act additively in terms of therapeutic effectiveness, meaning that using multiple types of sulfonamides decreases likelihood of drugs crystallizing while increasing therapeutic effectiveness

trimethoprim

bacteriostatic/bactericidal dihydrofolate analog that inhibits dihydrofolate reductase with a high affinity for the bacterial enzyme relative to the mammalian isoform that is often used in combination with sulfonamides because significantly higher concentration of _____ is required to produce therapeutic effect without sulfonamide inhibition of dihydrofolic acid synthesis

trimethoprim resistance

_____ develops due to increased dihydrofolate reductase expression or reduced binding of _____ to the enzyme

penicillin

widely used antibiotic derived from mold that inhibits cross linking of bacterial cell wall units by binding to PBP1 (penicillin binding protein 1), inhibiting synthesis of bacterial cell wall; autolysins cleave previously synthesized cell wall to create weak points, leading to membrane rupture

cephalosporins

penicillinase-resistant antibiotics derived from fungus that are similar to penicillins but are more effective against gram negative bacteria; used prophylactically for surgeries

cephalosporin resistance

_____ can develop due to alterations in antibiotic binding proteins or production of metabolic enzymes (cephalosporinases and beta-lactamases)

vancomycin

glycopeptide antibiotic used to treat life-threatening infections caused by gram positive bacteria unresponsive to other antibiotics (ex: MRSA) that binds to bacterial cell wall polymer to prevent cross linking; used only when other antibiotics do not work due to high toxicity

carbapenem

beta-lactam antibiotic that binds to PBPs to prevent cross linking of bacterial cell well to kill both gram positive and gram negative bacteria; used in cases of cephalosporin-resistance

fluoroquinolones

broad spectrum, potent antibiotics that can be given orally and are less susceptible to resistance; inhibit bacterial topoisomerase IV to target gram positive bacteria and DNA gyrase to target gram negative bacteria which inhibits ability to re-ligate DNA breaks that are made to relieve supercoiling (bactericidal); ex: ciprofloxacin is used to treat anthrax poisoning

protein synthesis inhibitors

drugs that inhibit protein synthesis with varying selectivities for bacterial ribosomes

protein synthesis

-DNA transcribed into mRNA and tRNA

-mRNA combines with ribosome where charged tRNA binds to A site, which catalyzes formation of peptide bond via peptidyl transferase

-nascent polypeptide group translocates from A site to P site until stop codon is reached at which point termination occurs

bacteriostatic, bactericidil

_____ protein synthesis inhibitors include tetracyclines, chloramphenicol, erythromycin, while _____ protein synthesis inhibitors include aminoglycosides

aminoglycosides

bactericidal protein synthesis inhibitors that interfere with bacterial protein function, leading to membrane lysis

protein synthesis inhibitor resistance

_____ can develop due to reduced drug uptake, increased drug efflux, synthesis of ribosomal protection proteins, and enzymatic inactivation

why fungal infections can be difficult to treat

-relative similarity between fungal cells and animal cells

-slow growth rate

-infection in poorly vascularized tissues

-differences in cell walls of fungal compared to bacteria

fungal infections

_____ are more likely to occur during cancer treatment, in HIV patients, after organ transplants, or in hospital settings due to use of broad spectrum antibiotics

amphotericin B

broad spectrum antifungal used for severe systemic infections that binds to ergosterol and forms pores in membrane, leading to cell leakage; only administered in hospitals due to high toxicity (can lead to fevers and eventually irreversible nephrotoxicity)

amphotericin B resistance

_____ can develop due to reduced binding affinity to ergosterol via sterol alterations

Nystatin

antifungal similar to amphotericin B that is used topically (toxic systemically)

azoles

broad spectrum fungistatic drugs that inhibit ergosterol synthesis

flucytosine

antifungal that is converted FdUMP, which inhibits thymidylate and DNA synthesis

Griseofulvin

antifungal that interferes with microtubule function; resistance can develop due to reduced affinity for microtubule proteins