ANTIBIOTIC

MECHANISMSKimberly M. Treier

PharmD Candidate 2016

Albany College of Pharmacy and Health

Sciences

Three Primary Targets

• Bacterial

• Cell Envelope

• Protein Synthesis

• Replication

Bacterial Cell Envelope

Cell Envelope

• Peptidoglycan layer:

• Repeating units of N-acetylglucosamine and

N-acetylmuramic acid

• Pentapeptide side chains ending in D-alanine –

D-alanine

• Penicillin-binding protein (PBP) crosslinks to N-

acetylmuramic acid via removal of terminal D-

alanine

• Rigidity = cellular structure

• NOT in human cells = good target

• Differ between gram positive (GPB) and gram

negative bacteria (GNB)

Cell Envelope

• Binding to PBP active site

• β-lactams

• Penicillins

• Cephalosporins

• Carbapenems

• Monobactams

• Binding to D-Ala-D-Ala

• Glycopeptides

• Vancomycin

• Telavancin

• Additional MOA: lipophilic tail penetrates membrane

• Dalbavancin (under FDA review)

Inhibit terminal transpeptidation

step

Cell Envelope

• Resistance: the Six P’s

1. Penetration into human cells• Rickettsia, Legionella

2. Porins (GNB)• Escherichia coli, Proteus mirabilis

3. Pumps (GNB)• Pseudomonas aeruginosa

4. Penicillinases (β-lactamases)• Staphylococcus, Nesseria,

Haemophilis species

5. PBPs• Bacteroides fragilis

6. Peptidoglycan• Mycoplasma, Chlamydia species

Cell Envelope

• Resistance: the Six P’s

1. Penetration into human cells• Rickettsia, Legionella

2. Porins (GNB)• Escherichia coli, Proteus mirabilis

3. Pumps (GNB)• Pseudomonas aeruginosa

4. Penicillinases (β-lactamases)• Staphylococcus, Nesseria,

Haemophilis species

5. PBPs• Bacteroides fragilis

6. Peptidoglycan• Mycoplasma, Chlamydia species

Considerations

• Most β-lactams cannot penetrate human cells (i.e. intracellular

pathogens)

• Easier for β-lactams to inhibit GPB (more accessible peptidylglycan

layer)

• Different β-lactam side chains = altered spectrum of activity

• Penicillins have 1 variable R group:

• Bulky R group = resistance to β-lactamases

(antistaphylococcal penicillins)

• Hydrophilic R group = passage through porins

(aminopenicillis)

• Cephalosporins have 2 variable R groups:

• Anaerobic activity (cefamycins)

• Antipseudomonal and antistaphylococcal activity (cefepime)

• MRSA activity (ceftaroline)

• Carbapenems have broad range of activity: enhanced porin

penetration (small molecules), resistance to β-lactamases and affinity

for broad range of PBPs

• Aztreonam: only active against GNB

• Glycopeptide antibiotics: are very large only active against GPB

Cell Envelope

• Pore formation

• Cyclic lipopeptide

• Daptomycin

• Semisynthetic lipoglycopeptide

• Telavancin

Membrane disruption

• Increased permeability

• Cationic cyclic decapeptide

• Colistin

Cell Envelope

• Pore formation

• Cyclic lipopeptide

• Daptomycin

• Semisynthetic lipoglycopeptide

• Telavancin

Membrane disruption

• Increased permeability

• Cationic cyclic decapeptide

• Colistin

Considerations

• Daptomycin: cannot penetrate GNB outer membrane only active

against GPB

• Colistin: binds to lipopolysaccharide molecules only active against

GNB

Cell Envelope

• Inhibition of N-acetylmuramic acid precursor• Phosphoenolpyruvate analog

• Fosfomycin

• Inhibition of lipid carrier cycling of peptidylglycansubunits• Cyclic peptide

• Bacitracin

• Inhibition of D-alanine addition to peptidoglycan pentapeptide• D-alanine analog

• Cycloserine

Inhibition of early cell wall

synthesis

Protein Synthesis

• Lodging within the DNA/RNA tunnel

• Rifampin and Rifamycins

• Rifampin

• Rifabutin

• Rifapentine

• Rifaximin

Inhibition of bacterial RNA

polymerase

Protein Synthesis

• Lodging within the DNA/RNA tunnel

• Rifamycins

• Rifampin

• Rifabutin

• Rifapentine

• Rifaximin

Inhibition of bacterial RNA

polymerase

Considerations

• Resistance develops very easily (only requires one amino acid

substitution) often given with other agents

• Usually utilized for mycobacterial and staphylococcal infections

Protein Synthesis

• Prevent tRNA entry

• Tetracyclines

• Tetracycline

• Doxycycline

• Minocycline

• Glycyclines

• Tigecycline

Inhibition of bacterial ribosome:

30S subunit

Protein Synthesis

• Prevent ribosomal

complex formation,

mRNA reading and

movement

• Amimoglycosides

• Gentamycin

• Tobramycin

• Amikacin

• Streptomycin

• Kanamycin

• Netilmicin

Inhibition of bacterial ribosome:

30S subunit

Protein Synthesis

• Prevent ribosomal

complex formation,

mRNA reading and

movement

• Amimoglycosides

• Gentamycin

• Tobramycin

• Amikacin

• Streptomycin

• Kanamycin

• Netilmicin

Inhibition of bacterial ribosome:

30S subunit

Considerations

• Passage through bacterial cytoplasmic membrane requires oxygen-

and proton-dependent active transport

• Excellent activity against aerobic bacteria (e.g.

Enterobacteriaceae and P. aeruginosa)

• Poor activity against anaerobic bacteria and acidic environments

(e.g. abscess)

• Aerobic GPB activity enhanced by synergistic antibiotics inhibiting cell

wall synthesis

• Aminoglycosides often used with another antibiotic

Protein Synthesis

• Prevent aminoacyltranslocation• Macrolides

• Erythromycin

• Clarithromycin

• Azithromycin

• Ketolides

• Telithromycin

• Chloramphenicol

• Lincosamides

• Clindamycin

• Streptogramins

• Quinupristin/Dalfopristin

Inhibition of bacterial

ribosome: 50S subunit

Protein Synthesis

• Prevent aminoacyltranslocation• Macrolides

• Erythromycin

• Clarithromycin

• Azithromycin

• Ketolides

• Telithromycin

• Chloramphenicol

• Lincosamides

• Clindamycin

• Streptogramins

• Quinupristin/Dalfopristin

Inhibition of bacterial

ribosome: 50S subunit

Considerations

• Telithromycin: active against many macrolide-resistant bacteria due

to tighter ribosomal binding and resistance to efflux pumps

• Clindamycin: most GNB are intrinsically resistant due to inability to

penetrate the outer membrane

• Quinupristin/Dalfopristin:

• Dalfopristin causes ribosomal conformational change

enhanced quinupristin binding

• Share same binding region as macrolides and clindamycin

potential cross-resistance

Protein Synthesis

• Binding to 23S subunit

• Oxazolidinone

• Linezolid

• Tedizolid (in development)

• Unknown

• Nitrofurans

• Nitrufurantoin

• Additional mechanism: inhibition of bacterial acetyl CoA and carbohydrate

metabolism

Inhibition of bacterial ribosome

Protein Synthesis

• Binding to 23S subunit

• Oxazolidinone

• Linezolid

• Tedizolid (in development)

• Unknown

• Nitrofurans

• Nitrufurantoin

• Additional mechanism: inhibition of bacterial acetyl CoA and carbohydrate

metabolism

Inhibition of bacterial ribosome

Considerations

• Linezolid: E. coli intrinsically resistant due to efflux pumps

• Nitrofurantoin: high accumulation in urine but low accumulation in

blood not used for pyelonephritis because infection usually spreads

to the blood

Bacterial Replication

• Inhibit dihydropteroate synthase

• Sulfonamides

• Sulfamethoxazole

• Dapsone

• Inhibit dihydrofolate

reductase

• Non-sulfonamides

• Trimethoprim

Inhibition of folate synthesis

Bacterial Replication

• Inhibit DNA gyrase and

topoisomerase IV

• Fluoroquinolones

• Ciprofloxacin

• Levofloxacin

• Gemifloxacin

• Moxifloxacin

• Generation of free

radicals

• Small molecule

• Metronidazole

DNA strand breakage

Bacterial Replication

• Inhibit DNA gyrase and

topoisomerase IV

• Fluoroquinolones

• Ciprofloxacin

• Levofloxacin

• Gemifloxacin

• Moxifloxacin

• Generation of free

radicals

• Small molecule

• Metronidazole

DNA strand breakage

Considerations

• Metronidazole: can only generate free radicals via metabolic

processes in anaerobic bacteria not active against aerobic bacteria

Mycobacterium

• Inhibition of mycolic acid

• Isoniazid

• Pyrazinamide

• Inhibition of bacterial RNA polymerase

• Rifamycins

• Rifampin

• Rifabutin

• Rifapentine

• Inhibition of bacterial ribosomes

• Clarithromycin

• Azithromycin

Mycobacterium

• Inhibition of mycolic acid

• Isoniazid

• Pyrazinamide

• Inhibition of bacterial RNA polymerase

• Rifamycins

• Rifampin

• Rifabutin

• Rifapentine

• Inhibition of bacterial ribosomes

• Clarithromycin

• Azithromycin

Considerations

• Mycobacterium challenges:

• GPB but with gram positive and gram negative characteristics

• Peptidylglycan later containing long mycolic acids

• Outer membrane with porins distinct from other GNB

• Slowly dividing

• Long duration of treatment

• Most antibiotics effective in rapidly dividing bacteria

References

• Alan R. Hauser. Antibiotic Basics for Clinicians, Second

Edition. Baltimore, Maryland. Lippincott Williams &

Wilkins; 2013.

• Bertram G. Katzung, Anthony J. Trevor: Basic & Clinical

Pharmacology, 13th Ed. www.accesspharmacy.com.

• Clinical Pharmacology [database online]. Tampa, FL: Gold

Standard, Inc.; 2016. URL:

http://www.clinicalpharmacology.com.

• Silhavy TJ, Kahne D, Walker S. The Bacterial Cell

Envelope. Cold Spring Harb Perspect Biol. 2010 May;

2(5): a000414. Doa: 10.1101/schperspect.a000414.