microbio chapter 20

walter white

selective toxicity

selectively finding and destroying pathogens without damaging the host

chemotherapy

the use of chemicals to treat a disease

antimicrobial drugs

substances that in small amounts kill or inhibit the growth of microbes, including bacteria, fungi, viruses, and parasites

antibiotics

specific type of antimicrobial drug that target bacteria

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 (flourish) of an opportunistic pathogen when the normal microbiota are disrupted, typically due to antibiotic use

• e.g.,

  • candida albicans

  • clostridioides difficile

bactericidal

kill bacteria directly

• e.g., penicillin, cephalosporins

bacteriostatic

prevent bacteria from growing but do not kill them

• e.g., tetracyclines

major action nodes of antibacterial drugs

• inhibition of cell wall synthesis

• inhibition of protein synthesis (translation)

• inhibition of nucleic acid replication and transcription

• injury to plasma membrane

• inhibition of essential metabolite synthesis

inhibition of cell wall synthesis

• penicillins prevent the synthesis of peptidoglycan

• generally safe and effective → but can still have side effects

  • penicillin, cephalosporins, bacitracin, vancomycin

inhibition on protein synthesis

• target bacterial 70S ribosomes

• have side effects

  • chloramphenicol, erythromycin, tetracyclines, streptomycin

inhibition of nucleic acid replication and transcription

• quinolones block topoisomerase (interferes with DNA replication)

• rifampin block RNA polymerase (interferes with transcription)

• can still have some effects

  • quinolones, rifampin

injury to plasma membrane

• polypeptide antibiotics change membrane permeability

• antifungal drugs combine with membrane sterols

• have side effects

  • polymyxin B

inhibition of essential metabolite synthesis

• antimetabolites compete with normal substrates for an enzyme

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

• can have some effects

  • sulfanilamide, trimethoprim

natural penicillins

inhibitors of bacterial cell wall synthesis

penicillin G

• against gram-positive bacteria, require injection

penicillin V

• against gram-positive bacteria, oral administration

semisynthetic penicillins

inhibitors of bacterial cell wall synthesis

oxacillin

• narrow spectrum, resistant to penicillinase

ampicillin

• broad spectrum

amoxicillin

• broad spectrum; combined with inhibitor of penicillinase

cephalosporins

cephalothin

• first-generation cephalosporin; activity similar to penicillin; requires injection

ceftaroline

• fifth-generation cephalosporin; activity against MRSA

polypeptide antibiotics

bacitracin

• against gram-positive bacteria; topical application

vancomycin

• a glycopeptide type; penicillinase resistant; against gram-positive bacteria

antimycobacterial antibiotics

isoniazid

• inhibit synthesis of mycolic acid component of cell wall of mycobacterium spp.

inhibitors of protein synthesis

chloramphenicol

• broad spectrum, potentially toxic

aminoglycosides

streptomycin

• broad spectrum, including mycobacteria

gentamicin

• broad spectrum, including pseudomonas spp.

tetracyclines

tetracycline, oxytetracycline, chlortetracycline

• broad specturm, including chlamydias and rickettsias

macrolides

erythromycin

• alternative to penicillin

lipopeptides

daptomycin

• to treat MRSA infections

polymyxin B

• topical use, gram-neg bacteria (including psuedomonas spp.

rifamycins

rifampin

• inhibits synthesis of mRNA; treatment of tuberculosis

quinolones/fluroquinolones

nucleic acid synthesis inhibitors

nalidixic acid, ciprofloxacin

• inhibit topoisomerase; broad spectrum; urinary tract infections

sulfonamides

competitive inhibitors of the synthesis of essential metabolites

sulfamethoxazole-trimethoprim

• broad spectrum; combination is widely used

polyenes

agents affecting fungal sterols (plasma membrane)

azoles

• clotrimazole

  • topical use

• ketoconazole

  • systemic fungal infections

allylamines

• terbinafine, naftifine

  • treatment of diseases resistant to azoles

entry and fusion inhibitors

antiviral drugs

maraviroc

• binds CCR5 of HIV

amantadine, zimantadine

widespread resistance in influenzavirus

zidovudine (AZT), tenofovir, emtricitabine

inhibit HIV reverse transcriptase

acyclovir, ganciclovir

used primarily against herpesviruses

ribavirin, iamivudine

used to treat hepatitis B and C

adefovir dipivoxil

treatment of iamivudine-resistant infections of hepatitis B virus

cidofovir

cytomegalovirus infections

nirametrelvir, ritonavir, molnupiravir (assembly and exit inhibitors)

SARS-CoV-2 protease inhibitors

saquinavir (assembly and exit inhibitors)

HIV protease inhibitor

zanamivir, oseltamivir, peramilvir (assembly and exit inhibitors)

inhibit neuraminidase of influenzavirus

alpha interferon

hepatitis B, C, D

chloroquine, mefloquine (antiprotozoan drugs)

malaria; effective against red blood cell stages

artemisinin (antiprotozoan drugs)

malaria

diidohydroxyquin (antiprotozoan drugs)

amebic infections; amebicidal

suramin (antiprotozoan drugs)

african trypanosomiasis

metronidazole, tinidazole (antiprotozoan drugs)

giardisis, amebiasis, trichomoniasis

miltefosine (antiprotozoan drugs)

amebic encephalitis

niclosamide (anthelminthic drugs)

prevents ATP generation in mitochondria, tapeworm infections

praziquantel (anthelminthic drugs)

alters plasma membrane, kills flatworms

pyrantel pamoate (anthelminthic drugs)

neuromascular block; kills roundworms

mebendazole, albendazole (anthelminthic drugs)

inhibit absorption of nutrients, intestinal roundworms

ivermectin (anthelminthic drugs)

paralyzes intestinal roundworms

penicillin

contains a beta-lactam ring

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

• prevent the cross-linking of peptidoglycans, interfering with cell wall construction

  • natural penicillin

  • semisynthetic penicillins

penicillinase-resistant penicillins

methicillin and oxacillin

broad-spectrum penicillins

effective against gram-positives and some gram-negatives

• e.g., amoxicillin/clavulanate (Augmentin)

penicllins plus beta-lactamase inhibitors

contain clavulanic acid, a noncompetitive inhibitor of penicillinase

cephalosporins

work similar to penicillins

• beta-lacatam ring differs from penicillin

• grouped according to their generation of development

disk-diffusion method (kirby-bauer test)

tests the effectiveness of chemotherapeutic agents

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

zone of inhibition

measured around the disk; determines the susceptibility of the organism to the antibiotic

epsilometer test (E test)

a gradent diffusion method that determines antibiotic sensitivity and estimates minimal inhibitory concentration (MIC)

• lowest antibiotic concentration preventing bacterial growth

broth dilution tests

determines 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

• subculture is used to determine whether bacteria have been killed or only inhibited

superbugs

bacteria that are resistant to multiple antibiotics, making them difficult to treat

• e..g, methicillin-resistant staphylococcus aureus (MRSA)

• resistance genes are often spread horizontally among bacteria on plasmids or transposons

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

  • acinetobacter baumannii

  • psuedomonas aeruginosa

  • some members of the enterobactericeae

mechanims of resistance

1. enzymatic destruction or inactivation of the drug

2. prevention of penetration to the target site within the microbe

3. alteration of the drug’s target site

4. rapid efflux (ejection) of the antibiotic

5. variations of mechanisms of resistance

misuse of antibiotics

select for resistance mutants

misuse includes:

• availability of antibiotics without prescriptions in some countries

• using outdated or weakened antibiotics

• using antibiotics for the common cold and other inappropriate conditions

• using antibiotics in animal feed

• failing to complete the prescribed regimen

• using someone else’s leftover prescription

antibiotic safety

therapeutic index: risk versus benefit

reactions of antibiotics with other drugs

damage to organs

risk to the fetus

synergism

the effect of two drugs together is greater than the effect of either alone

• e..g, penicillin and streptomycin are much more effective when taken together in some situations

antagonism

the effect of two drugs together is less than the effect of either alone

• e..g, tetracycline sometimes interferes with activity of penicillin

future of antimicrobial agents

• target virulence factors

• sequester iron, which feeds pathogens

• seek drugs that combat dormant persister cells

• need more drugs to target gram-negative bacteria

• need ways to test the antimicrobial sensitivity of nonculturable bacteria

antimicrobial peptides

produced by various organisms

• bacteriocins: antimicrobial peptides produced by bacteria to inhibit the growth of closely related or competitive bacterial strains

phage therapy

using the bacteriophage to treat infections