MedChem of Agents Acting on Cell Walls & Membranes

Lactam

cyclic amide

Penicillin-binding Protein (PBP)

- type of transpeptidase enzyme involved in crosslinking peptidoglycan chains in the bacterial cell wall

- drug target of beta-lactam antibiotics

Siderophore

iron-chelating compound, strategy used to enhance gram (-)

Current CWM agents

- agents interfering with the synthesis of cell wall precursors starting materials

- inhibits the formation/elongation of petidoglycan chains

- agents inhibiting the cross-linking of peptidoglycan chains (PBP/transpeptidase inhibitors)

- agents used in combo with beta-lactam antibiotics

- agents acting on other cell wall & membrane targets

Agents Targeting CWM Precursors: interfere with synthesis of cell wall precursors

- clycloserine

- fosfomycin

Fosfomycin CC

epoxide or phosphonic acid (phosphoenolpyruvate analog)

Cycloserine CC

cyclic amino acid (D-alanine analog)

MOA of cycloserine

inhibits alanine racemase & D-Ala-D-Ala ligase

MOA of fosfomycin

inhibits enolpyruvate transferase

Spectrum of cycloserine and fosfomycin

both agents have borad-spectrum effects on both Gram(+) and Gram(-) microorganisms

Cycloserine activity

- can be either bactericidal or bacteriostatic

- concentration-dependent

Fosfomycin activity

bactericidal when used at therapeutic doses

ADRs of cycloserine

- nasty side-effect profile (d/t partial agonism at CNS NMDA receptors)

- includes acute psychosis & convulsions

- not really used

ADRs of fosfomycin

minimal, probably d/t single-dose regimen

T/F: Cycloserine is commonly used to treat uncomplicated UTIs

FALSE its rarely used d/t side effect profile

Uses of cycloserine and fosfomycin

- cycloserine is typically limited to second-line therapy for resistant M. tuberculosis infections

- fosfomycin usually limited to second- or third-line therapy for uncomplicated UTIs

Agents inhibiting the formation/elongation of peptidoglycan chains: Chain inhibitors

- Cyclic peptides: bacitracin

- glycopeptides/lipoglycopeptides: vancomycin, dalbavancin, oritavancin, telavancin

Chain inhibitor agents

- bacitracin

- dalbavancin

- oritavancin

- telavancin

- vancomycin

SAR of bacitracin & vancomycin

- natural products

- newer glycopeptides have lipophilic additions to improve PK profiles

MOA/PC of bacitracin

prevents dephosphorylation of lipid carrier that transfers peptidoglycan subunits to the cell wall

MOA/PC of glycopeptides

bind to D-Ala-D-Ala subunits, preventing transglycosylation & transpeptidation

Spectrum of bacitracin

primarily gram (+)

Spectrum of glycopeptides

gram (+) incl. MRSA

Activity of bacitracin

bactericidal

Activity of Glycopeptides

usually bactericidal against susceptible microorganisms ("last resort" agents)

Why does bacitracin have minimal toxicity?

d/t topical usage

Glycopeptides ROA

PO (vancomycin) and IV (vanco, dalba, ortia, tela)

When administered orally, the BA of vancomycin is less than ____________, making it ineffective for treating _______________

- less than 10%

- ineffective for treating systemic infections

ADRs of vancomycin

- anaphylaxis

- red-man syndrome

- nephrotoxicity

- ototoxicity (can be permanent)

Telavancin BBW

increased mortality in HABP/VABP pts w/ pre-existing moderate-severe renal impairment, nephrotoxicity, and embrofetal toxicity

Typical usage of bacitracin

topical wound care

What is PO vancomycin used for? What is IV vancomycin used for?

- PO for treatment of C. diff diarrhea & enterocolitis d/t S. aureus

- IV for treatment of various serious infections incl. septicemia, endocarditis, SSTIs, bone infections, LRTIs

What are dalbavancin, ortavancin, and telavancin used for?

treating ABSSSIs caused by suscpetible gram (+) organisms in adult & pediatric pts

Bacitracin Characteristics

- PC/MOA: binds to undecaprenyl pyrophosphate

- CC: (mixture of) cyclic peptides

Glycopeptides characteristics

- PC/MOA: binds to D-Ala-D-Ala subunits

- CC: glycopeptide (natural product)

Cross-Linking Inhibitors: Inhibit cross-linking of peptidoglycan chains

- Beta-lactams, including:

- penicillins

- cephalosporins

- carbapenems & thiopenems

- monobactams

Penicillin CC

beta-lactams

SAR of penicillin: Fundamental requirements for beta-lactam antibiotic activity

- highly-constrained, fused B-lactam* structure

- carboxylic acid (or similar acidic) group at C3

- substituted amide side chain --> g-APA inactive*

Groups of penicillins

- natural (or fermentation-derived) penicillins

- anti-staphylococcal (penicillinase-resistant) penicillins

- extended-spectrum penicillins (amoxicillin)

- combinations w/beta-lactamase inhibitors

Natural (or fermentation-derived) penicillins

- PO, IV, IM (depot preps)

- penicillin G, penicillin V

- bactericidal

- spectrum: primarily non-lactamase-producing Gram(+) cocci, still used as first-line therapy

- sensitive to beta-lactamases

- ADRs primarily limited to hypersensitivity and injection-site reactions

Extended-spectrum penicillins

- PO & IV

- ureido-(piperacillin)

- amino-(ampicillin, amoxicillin)

- sensitive to beta-lactamases

- ADRs primarily limited to hypersensitivity, injection-site reactions, and GI upset

Extended-spectrum penicillins Usage: amoxicillins

primary drug of choice for the PO treatment of non-lactamase-producing infections by susceptible strains

Anti-staphylococcal penicillins

- PO (diclo) & IV (naf, oxa)

- bactericidal

- primarily used for susceptible Staph. infections

- nafcillin & the isoxazolyl penicillins (oxacillin, dicloxacillin)

- resistant to some beta-lactamases

- ADRs primarily limited to hypersensitivity and injection-site reactions

Anti-staphylococcal penicillins: What structure change yields lactamase resistance?

increased steric bulk

Usage of Anti-staphylococcal Penicillins

primarily used in cases where penicillinase-producing infections prevent the use of natural PCNs

T/F: Newer generation cephalosporins typically have better resistance to beta-lactamases and better Gram(-) coverage

TRUE

1st generation cephalosporins

- PO, IV, IM

- bactericidal

- primarily non-lactamase-producing Gram(+)

- sensitive to beta-lactamases

- used as second- or third-line therapy for susceptible infections

- ADRs primarily limited to hypersensitivity & injection-site reactions

- cephalexin, cefadroxil, cefazolin

1st generation cephalosporin spectrum

primarily non-lactamase-producing Gram(+)

2nd generation cephalosporins

- PO, IV, IM

- bactericidal

- used as second- or third-line therapy for susceptible infections

- sensitive to some beta-lactamases

- ADRs primarily limited to hypersensitivity & injection-site reactions

- cefaclor, cefotetan, cefuroxime, cefoxitin, cefproxil

Cephamycins have a __________________ group that increases resistance

7-alpha-methoxy group

3rd-generation cephalosporins

- PO, IV, IM

- bactericidal

- sensitive to some beta-lactamases (oximes increase resistance)

- several agents are first-line therapy for different types of infections

- ADRs primarily limited to hypersensitivity & injection-site reactions

- cefpodoxime, cefixime, cefdinir, ceftriaxone, cefotaxime, ceftazidime, cefditoren

3rd-generation cephalosporins: What increases resistance to some beta-lactamases?

oximes

4th generation cephalosporins

- IV, IM

- oximes incr. resistance to beta-lactamases

- bactericidal

- potential second- or third-line therapy for infections d/t susceptible microorganisms

- ADRs primarily limited to hypersensitivity & infection-site reactions

- cefepime

4th generation cephalosporins spectrum

similar to 3rd gen, but with better Gram(-) coverage & lactamase resistance

5th generation cephalosporins

- IV

- oximes incr. resistance to beta-lactamases

- bactericidal

- used as potential second- or third-line therapy for infections d/t susceptibel microorganisms

- ADRs primarily limited to hypersensitivity & injection-site reactions

- ceftaroline, ceftobiprole, ceftolozane

5th-generation cephalosporin spectrum

similar to 3rd & 4th gen agents, but with better Gram(-) coverage & lactamase resistance

Cefiderocol

- IV

- uses a siderophore as a "Trojan horse" to enhance penetratoin into Gram(-) bacteria

- bactericidal

- ADRs primarily infusion-site reactions, GI distress

- used for the treatment of susceptible Gram(-) infections (HABP/VABP, UTIs) in adult pts

Cefiderocol spectrum

Gram(-)

Carbapenems

- IV, NOT orally active

- BROAD

- inhibits some beta-lactamases

- bactericidal

- ADRs infusion-site reactions most common

- used for second- or third-line therapy for severe infections by susceptible organisms

Carbapenems spectrum

- among the widest spectrum of activity

- ULTRA-BROAD

Imipenem is deactivated by renal dehydropeptides, so it is used in combination with....

cilastatin

1st generation carbapenem

imipenem

2nd generation carbapenem

- meropenem

- ertapenem

SAR of carbapenems: What conders resistance to renal dehydropeptidases?

4-B-methyl group confers resistance to renal dehydropeptidases

Monobactams

- IV, IM, or Inh.

- aztreonam

- bactericidal

- used as possible second- or third-line option for severe infections by susceptible strains

- ADRs minimal, but primarily limited to ROA issues

- have good CNS penetration

Monobactams are resistnat to __________________, but susceptibel to _________________________

- beta-lactamases

- hydrolysis by BSLs and ESBLs

Beta-Lactamase characteristics

- PC/MOA: PBP inhibitor

- CC: beta-lactam with either penam core, cefem core, carbapenem core, monobactam core

Beta-lactamase Inhibitors

- avibactam

- vlavulanic acid

- durlobactam

- enmetazobactam

- relebactam

- sulbactam

- tazobactam

- vaborbactam

Beta-lactam-based Beta-lactamase Inhibitors

- clavulanic acid

- enmetazobactam

- sulbactam

- tazobactam

Diazabicyclooctane-based beta-lactamase Inhibitors

- avibactam

- durlobactam

- relebactam

Boronic-acid-based beta-lactamase Inhibitors

vaborbactam

MOA of beta-lactamase inhibitors

- beta-lactams- covalent irreversible inhibition

- boronic acids, diazabicyclooctanes- covalent reversible inhibitions

Beta-lactamase Inhibitors activity

- designed to slow metabolism of beta-lactam-based antibiotics

- may have some antibiotic (PBP-inhibiting) effects on their own (sulbactam)

ADRs of beta-lactamase inhibitors

GI upset (N/D) common

Beta-lactamase inhibitor characteristics

- PC/MOA: beta-lactamase inhibitor

- CC: beta-lactam

Agents that act on the cell membrane

- lipopeptides: daptomycin

- polymyxins: polymyxin B, colistimethate

- both are bactericidal

MOA of daptomycin

causes membrane depolarization & blocks cell wall synthesis

MOA of polymyxins

causes membrane disruption

Spectrum of daptomycin

primarily on Gram(+)

Spectrum of polymyxins

primarily on Gram(-)

Daptomycin

- IV

- ADRs incl. possible myopathy

- used as possible second-line therapy for various infections, especially in cases of vancomycin resistance

Polymyxins

- ophthalmic, otic, topical

- ADRs minimal d/t ROA

- used topically (in combo) for wound care; via opthalmic & otic routes for eye & ear infections

Identify the major limitation associated with the systemic use of many antibiotics based on cyclic peptides

- systemic toxicity

- limited BA (PO vanco BA <10%)

Identify the chemical features of beta-lactam antibiotics that resemble the D-Ala-D-Ala dipeptide

- beta-lactam ring

- carboxylic acid group

- spatial arrangement

- substituted side chain

Briefly explain the major SAR points of the beta-lactam antibiotics

• a highly-constrained, fused β-lactam* structure

• carboxylic acid (or similar acidic) group at C3

• substituted amide side chain --> 6-APA inactive*Briefly

Why are beta-lactam antibiotics not typically stored or shipped as aqueous solutions?

- beta-lactam hydrolysis

- water reacts w/ beta-lactam and opens ring. once water is added, breakdown starts

What is the structural feature in anti-staphylococcal penicillins that confers resistance to some beta-lactamases?

increased steric bulk in the amide side chain

What is the structural feature in 2nd- generation CARBAPENEMS that confers resistance to renal dehydropeptidases?

4-β-methyl group confers resistance to renal dehydropeptidases

The different β-lactam cores