Chapter 14: Antimicrobial Drugs (Final)

contributors to chemotherapy

paul ehrlich and alexander fleming

selective toxicity

selectively finding and destroying pathogens without damaging the host

chemotherapy

the use of chemicals to treat a disease

antibiotic

a substance produced by a microbe that, in small amounts, inhibits another microbe

antimicrobial drugs

synthetic substance that interfere with the growth of microbes

fleming discovered

penicillin in 1928

protosil red dye (a type of sulfanilamide) used for streptococcal infections in 1932

first clinical trials for penicillin in 1940

narrow-spectrum of microbial activity

drugs that affect a narrow range of microbial types

broad-spectrum antibiotics

affect a broad range of gram-positive or gram-negative bacteria

superinfection

overgrowth of normal microbiota that is resistant to antibiotics

e.g. Candida albicans, Clostriodiodes difficile

development of superinfections

1. normal microbiota keeps opportunistic pathogens in check

2. broad-spectrum antibiotics kill nonresistant cells

3. drug-resistant pathogens proliferate and can cause a superinfection

dosage

amount of medication given during a certain time interval

children- dosage based on mass

adults- standard dosage, independent of mass

consider half life

intravenous (IV) administration

concentration peaks very quickly and then gradually decreases

oral or intramuscular (IM) administration

it takes longer for the concentration to reach its peak

bactericidal

kill microbes directly

bacteriostatic

prevent microbes from growing

bacteriolytic

rupture cytoplasm membrane, total cell count goes down

major actions modes of antibacterial drugs

inhibition of...

1. cell wall synthesis

2. protein synthesis

3. nucleic acid replication and transcription

4. essential metabolite synthesis

5. injury to plasma membrane

inhibiting cell wall synthesis

penicillins prevent the synthesis of peptidoglycan

growing cells

inhibiting protein synthesis

target bacterial 70s ribosomes

chloramphenicol, streptomycin, tetracyclines

chloramphenicol

binds to 50s portion and inhibits formation of peptide bond

tetracyclines

interfere with attachment of trna to mrna-ribosome complex

streptomycin

changes shape of 30s portion, causing code on mrna to be read incorrectly

injuring the plasma membrane

polypeptide antibiotics change membrane permeability

antifungal drugs combine with membrane sterols (absent in bacteria)

ioniphore

ionophores

antibiotics that allow uncontrolled movement of cations (not for human use)

cattle- digestive and growth

inhibiting nucleic acid synthesis

block topoismerase (interfere with dna replication)

block rna ploymerase (interfere with transcription)

inhibiting the synthesis of essential metabolites

antimetabolites compete with normal substrates for an enzyme

e.g. sulfanilamide

sulfanilamide

competes with para-aminobenzoic acid (PABA) stopping the synthesis of folic acid

penicillin-binding proteins

enzymes that produce peptide cross-links in peptidoglycan

penicillin

contain B-lactam ring

types are differentiated by the chemical side chains attached to the ring

prevent cross-linking of peptidoglycans, interfering with cell wall construction (esp gram-positives)

B-lactamase

breaks a bond in the B-lactam ring of penicillin to disable the molecule

bacteria with this enzyme can resist the effects of penicillin and some other B-lactam antibiotics

cycloserine

inhibits enzymes that make part of the peptide side chain on NAM

bacitracin

binds to the bactoprenol lipid carrier

transport of disaccharide units of peptidoglycan across the cell membrane to the growing chain inhibited

penicillin, vancomycin, and cephalosporins

inhibit the activity of enzymes that cross-link peptide side chains

natural penicillins

extracted from Penicillium fungi cultures

narrow spectrum of activity (G-injected, V-roal)

susceptible to penicillinases (B-lactamases)

semisynthetic penicillins

contain chemically added side chains, making them resistant to penicillinases

cephalosporins

work similar to penicillins

B-lactam ring differs from penicillin

grouped according to their generation of development

generations

4th gen- cephalosporins can cover pseudomonas

5th gen- MRSA

polypeptide antibiotics

bacitracin, vancomycin, teixobactin

bacitracin (PA)

topical application, works against G+

vancomycin

last line against antibiotic-resistant mrsa

problem- development of vrsa (mrsa that are also resistant to vacomycin) and vre (vancomycin resistant enterococcus)

teixobactin

works against resistant gram-positives (S.aureus, M.tuberculosis, VRE)

antimycobacterial antibiotics

isoniazid and ethambutol

isoniazid

inhibits the mycolic acid synthesis in mycobacteria

ethambutol

inhibits incorporation of mycolic acid into the cell wall

nitrofuratoin

converted to intermediates that attack bacterial ribosomal proteins

synthesized chemically

treatment for urinary bladder infections

chloramphenicol use

synthesized chemically, broad spectrum

can suppress bone marrow and affect blood cell formation (aplastic anemia)

aminoglycosides

amino sugars linked by glycoside bonds

change the shape of the 30s subunit of the 70s ribosome

can cause auditory damage and kidney damage

streptomycin, neomycin, gentamicin, tobramycin

tetracyclines use

produced by Streptomyces spp.

interfere with the trna attachment to ribosomes

broad spectrum, penetrate tissues, making them vulnerable against rickettsias and chlamydias

can supress normal interstinal microbiota resulting in superinfections, particularly with Candida albicans

glycylcyclines

broad spectrum, bacteriostatic

bind to 30s ribosomal subunit

inhibits rapid efflux, administered IV

used against mrsa and multi-drug resistant Acinetobacter baumanii

macrolides

contain a macrocyclic lactone ring

narrow spectrum against gram-positives (erythromycin)

newer drugs: fidaxomicin, azithromicin, clarithromycin

streptogramins

attach to the 50s subunit

work against gram-positives that are resistant to other antibiotics (mrsa)

synercid

oxazolidinones

bind to 50s/30s subunit interface

synthetic, combat mrsa (linezolid)

pleuromutilins

retapamulin: topical and effective against gram-positives

lipopeptides

daptomycin

ploymyxin B

plolymyxin E (colictin)

daptomycin

Attacks the bacterial cell membrane

produced by streptomycetes, used for skin infections

ploymyxin B

topical, combined with bacitracin and neomycin in nonprescription ointments, G-

bactericidal

polymyxin E (colictin)

effective against G-

rifemycin (rifampin)

inhibits RNA synthesis, penetrate tissues, antitubular activity

quinolon and fluoroquinlones

nalidixic acid

norfloxacin and ciproflaxacin

gemifloxacin, moxifloxacin

nalidixic acid

inhibits DNA gyrase, synthetic

norfloxacin and ciproflaxacin

nontoxic, broad spectrum

sulfonamides

inhibit the synthesis of folic acid, which is needed for nuliec acid and protein synthesis

similar to PABA (folic acid precursor)

competitvely binds to enzmye that converts PABA to dihydrofolic acid in the folic acid synthesis pathway

agents affecting fungal steroids

interrupt the synthesis of ergosterol, making the membrane excessively permeable

polyenes, azoles, allylamines

polyenes

nystatin: most commonly used

amphotericin B

amphotericin B

used for treatment of systemic fungal infections, toxic to the kidneys

imidazoles

topical, treat cutaneous mycoses

triazole

treat systemic fungal infections

allylamines

for azole-resistant infections

agents affecting fungal cell walls

echinocandins

echinocandins

inhibit the synthesis of B-glucan

agents inhibiting nucleic acids

flucytosine

flucytosine

cytosine analog interferes with rna synthesis

grisefulvin

produced by penicillium

inhibits microtubule formation

active against superficial dermatophytes

tolnaftate

for athletes foot

pentamidine

anti-pneumocystis, may bind to dna

entry and fusion inhibitors

block the receptors on the host cell that bind to the virus

block fusion of the virus and cell

uncoating, genome integration, and nucleic acid synthesis inhibitors

prevent viral uncoating

inhibit viral dna integration into the host genome

protease inhibitors

block the cleavage of protein precursors

example: paxlovid used to treat covid-19

exit inhibitors

inhibitor neuraminidase, an enzyme required for some viruses to bud from the host cell

interferons

produced by vira-infected cells to inhibit further spread of the infection

imiquimod- promotes interferon productions

antiretrovirals

for treating hiv/aids

quinine and chloroquine

treat malaria

artemisinin

kills plasmodium that causes malaria

metronidazole, tinidazole, nitazoxanide

also interferes with anaerobic bacteria

treats trichomonas, giardiasis, and amebic dysentery

miltefosine

inhibits cytochrome oxidase in mitochondria

treats amebic encephalitis and leishmaniasis

niclosamide

prevents atp production

treats tapeworms

praziquantel

alters membrane permeability

treats tapeworms and flukes

mebandazole and albendazole

interfere with nutrient absorption

treat intestinal helminths

ivermectin

paralysis of helminths

teats roundworms and mites

disk-diffusion method

kirby-bauer test

tests the effectiveness of chemotherapeutic agents

paper disks with a chemotherapeutic agent are placed on agar that has been inoculated with the test organism

zone of inhibition

zone of inhibition

around the disk determines the sensitivity of the organism to the antibiotic

e test

determines the minimal inhibitory concentration (mic)

lowest antibiotic concentration preventing bacterial growth

broth dilution tests

determine the mic and minimal bactericidal concentration (mbc) of an antimicrobial drug

test organism is placed into the wells of a tray containing dilutions of a drug, growth is determined

antobiograms

reports that record the susceptibility of organisms encountered clinically

minimum bactericidal concentration (mbc)

determined by using a tube dilution test and removing the antibiotic

requires further plating to determine if any cells survived

cells grow without antibiotic- bacteriostatic

cells of not grow, drug is bactericidal

persister cells

microbes with genetic characteristics allowing for their survival when exposed to an antibiotic

superbugs

bacteria that are resistant to large number. of antibiotics

bacterial pathogens that are resistant to nearly all antibiotics and cause healthcare-associated infections

acinetobacter baumannii

pseudomonas aeruginosa

members of the enterobacteriaceae

mechanisms of resitance

enzymatic destruction or inactivation of the drug

prevention of penetration to the target site within the microbe

alteration of the drug's target site

rapid efflux (ejection) of the antibiotic

variations of mechanism of resistance

beta lactamses

enzymes that break the B-lactam ring of penicillins and cephalosporins

often seen in G- bacteria