PCOL:3102 Antibacterials

drug classes and their drugs that are cell wall synthesis inhibitors

• beta-lactams

  • penicillins: penicillins, amoxcillin

  • cephalosporins: cefdinir

• non beta-lactams: vancomycin, bacitracin

• beta lactamase inhibitor: clavulanic acid

drug classes and their drugs that are protein synthesis inhibitors

• tetracyclines: doxcycline

• aminoglycosides: gentamicin

• macrolides: erythromycin

• lincosamide: clindamycin

• others include linezolid, mupirocin

generalizations of cell wall synthesis inhibitors

• maximum selective toxicity — good at targeting bacteria and not human cells

• inhibits peptidoglycan synthesis and its cross-links

• inhibits gram + >> gram -

• bactericidal

non-beta lactam drugs

• bacitracin

• vancomycin

bacitracin

• depletes lipid carrier for PDG synthesis

• toxic / bactericidal

• great for skin and eye infections

• usually topical cuz toxic if taken internally

• good in combo with polymyxin B

vancomycin

• reserved drug for serious infections

• blocks elongation and X-linking of PDG synthesis by binding the substrate

• bactericidal

• effective for gram + like MRSA (very narrrow spect)

toxicity for vancomycin

• ear and kidney toxicity

• vancomycin flushing syndrome (VFS)

beta-lactam drugs

ex. penicillins and cephalosporins

• have a beta-lactam ring that binds to penicillin binding protein (PBPs)

• inhibit the transpeptidases (PBPs) and block PDG strand X-linking

• bactericidal

• mainly gram +

how are beta-lactam resistance developed?

• bacteria can make beta-lactamases to break down the drug

• alteration of drug target (PBPs) to decrease affinity

• decrease drug influx so it can’t get in

• increase drug efflux so it’s pumped out

adverse effects of beta-lactams

• generally minimal

• allergy (usually delayed)

types of penicillins

• penicillin V

• amoxicillin

characteristics of penicillin V

• gram + and some gram - cocci

• first gen are mostly +++ but new gen includes + + / - -

• adverse effects: allergies and stevens johnson syndrome

amoxicillin

• extended spectrum penicillin

• + + / - -

• destroyed by beta-lactamases but can be overcome with combination therapy

what is used with amoxicillin to overcome beta-lactamases?

• clavulanic acid which is a beta-lactamase inhibitor

• lacks antibiotic activity alone

• doesn’t get degraded by beta-lactamase, just stops them (acts like a sponge)

cephalosporins

• inhibits cell wall synthesis

• large drug class, grouped into 5 gen

  • gen 1: excellent for +

  • gen 2, 3, 4: + + / - - but developed resistance

  • gen 5: developed against resistant strains like MRSA

• ex. cefdinir

cefdinir

• 3rd gen cephalosporin

• bacterial resistance cuz low PBP affinity

• very safe

• wide range of infections

bacterial vs human ribosome

bacteria: 70S ribosome with 30S + 50S (big) subunits

humans: 80S ribosome with 40S + 60S subunits

• tetracyclines

• aminoglycosides

50S ribosomal subunit inhibitor

• macrolides

• lincosamides

• oxazolidinones

• mupirocin → inhibits tRNA synthetase

tetracyclines

ex. doxycycline

• reversible binding to 30S subunit of bacterial ribosome

• bacteriostatic

• broad activity ( + + / - - ) → superinfection risk

• resistance by: poor uptake, increased efflux, drug inactivation, drug target alteration

aminoglycosides

ex. gentamicin

• bind irreversibly to the 30S ribosomal subunit

• inhibit protein synthesis at several levels

• bactericidal

• primarily gram -

  • if combined with cell wall synthesis inhibitor → gram +

• resistance: poor uptake but develops slowly

• adverse effects: ear and kidney toxicity

macrolides

ex. erythromycin

• binds reversibly to 50S subunit

• competitively inhibits ribosome binding of other protein synthesis inhibitors like clindamycin → antagonism

• bacteriostatic (cidal at higher conc)

• narrow spectrum: mostly gram +

• cross resistance with clindamycin and modified drug target and develops quickly

• can inhibit some CYPs

lincosamides

ex. clindamycin

• cross resistance with erythromycin cuz they bind to same spot

• narrow spect: mostly gram +

• bacteriostatic but can be cidal in some

• slow resistance

• great for bone infections but prone to C. dificile outgrowth

oxazolidinone

ex. linezolid

• binds to 23S rRNA of 50S subunit

• no cross resistance with other protein synthesis inhibitors

• bacteriostatic

• used for serious infections like MRSA

mupirocin

• inhibits tRNA synthetase

• ointment form since it would metabolized into inactive form if orally

• no cross resistance with other protein synthesis inhibitors

• used for MRSA or Grp A strep

folic acid synthesis inhibitors

ex. sulfonamides and trimethoprim

• act in sequential steps to block bacterial folic acid synthesis

• inhibits DNA, RNA, and protein synthesis

• high selective toxicity

• if administered alone = static BUT if you combine the two = cidal

sulfonamides

ex. sulfamethoxazole

• binds to DHPS enzyme to take the place of PABA in folic acid synthesis pathway to prevent DHFA synthesis

• competitive inhibitor

• high PABA levels inhibit sulfa activity

• bacteriostatic

• broad spect: + + / - - plus parasites NOT TICKS (cuz stimulates growth)

• cross-resistance to all sulfas

• resistace by: drug target amplifcation and alteration and increased efflux

trimethoprim

• takes DHFA place and competitively inhibits DHFR to make THFA

• bacteriostatic

• acts synergistically with sulfa → tmp-sulfa which is cidal

• broad spec: + + / - - but not all

• resistance by drug target amplification and alteration

tmp-sulfa common uses

• MRSA

• UTIs

fluoroquinolones

ex. ciprofloxacin

• great potency (well tolerated) and expanded spec: better gram + coverage

  • earlier ones better at gram -

• bactericidal

• target bacterial DNA synthesis by inhibiting bacterial DNA gyrase and topoisomerase to block DNA unwinding

• induces irreversible DNA dmg / degradation

• resistance by decreased drug influx, increased efflux, and drug target alteration

• mutation in both gyrase and topoisomerase causes high level of resistance

nucleic acid synthesis inhibitors

• sulfonamides

• trimethoprim

• fluoroquinolones

• rifampin

cell membrane inhibitors

• polymyxin B

• daptomycin

• pyrazinamide

polymyxin B

• detergent that disrupts cell membrane

• bactericidal

• topical use only cuz very toxic

• effective against gram neg

daptomycin

• membrane depolarization

• bactericidal

• treats MRSA (superior to linezolid)

metronidazole

• dna targeting agent

• selective reduction and accumulation of toxic products in anaerobes = disrupts bacterial DNA

• bactericidal

• preventative and treatment

antimycobacterial agents

• isoniazid

• rifampin

• pyrazinamide

• ethamutol

for TB

rifampin

• inhibits mRNA synthesis

• most effective cyz it inhibits bacterial RNA polymerase

• bactericidal

isoniazid

• inhibits cell wall synthesis

• bactericidal

• prodrug that is activated by mycobacterial enzyme

ethambutol

• inhibits cell wall synthesis

• bacteriostatic but cidal at high doses

• can cause red-green color blindness

pyrazinamide

• disrupts cell membrane

• prodrug activated by mycobacterial enzyme

• bactericdial

how to treat TB?

combination therapy is best way and is prolonged since it takes a long time for the microbe to grow and actually give you an effect