Antibiotic Resistance

The Miracle Revoked?

Wilson “Bill” Muse10/29/2009

Eukaryotes

Fungi

AzolesAllylamines

CycloheximidePolyenesPolyoxins

Nucleic acidanalogs

Echinocandins

Bacteria

Mycobacteria Gram-negativeBacteria

Gram-positiveBacteria

Obligately parasitic Bacteria

Chlamydia Rickettsia

Viruses

RNAviruses

DNAviruses

Tobramycin Penicillins

Streptomycin

SulfonamidesCephalosporins

Quinolones

Isoniazid

Tetracycline

VancomycinDaptomycin

Platensimycin

Polymyxins

Nucleoside analogsInterferon

Nonnucleosidereverse-transcriptase

inhibitorsProtease inhibitorsFusion inhibitors

The Miracle of Antibiotics

Classes of antibiotics• Aminoglycosides

• Tetracyclines

• Sulfonamides

• Quinolones

• Polypeptides

• B-lactams

• Macrolides

• Glycopeptides

• Cephalosporins

Antibiotic modes of action5 main targets

• Prevent cell wall synthesis (B-lactams)

• Disrupt membrane function (polymyxins)

• Prevent protein synthesis (chloramphenicols)

• Prevent nucleic acid synthesis (quinolones)

• Disrupt metabolic pathways (sulfanilamides)

Cell wall synthesis

CycloserineVancomycinBacitracinPenicillinsCephalosporinsMonobactamsCarbapenems

Folic acid metabolism

Quinolones Nalidixic acid

DNA gyrase

CiprofloxacinNovobiocin

TrimethroprimSulfonamides

DNA

THF

DHF

mRNA

50

30 30

50

Ribosomes

30

50

Cytoplasmic membranestructure and function

PolymyxinsDaptomycin

PABA Cytoplasmicmembrane

Cell wallPlantensimycin

Lipidbiosynthesis

Protein synthesis(tRNA)

MupirocinPuromycin

TetracyclinesSpectinomycinStreptomycinGentamicinKanamycinAmikacinNitrofurans

Lincomycin

Protein synthesis(30S inhibitors)

Erythromycin (macrolides)ChloramphenicolClindamycin

RifampinStreptovaricins

DNA-directed RNA polymeraseRNA elongation

Actinomycin

Protein synthesis(50S inhibitors)

Antibiotics: Mechanisms of ActionInhibition of Cell Wall Synthesis

-some antibiotics prevent peptidoglycan formation

Examples: vancomycin, amoxicillin, ampicillin, penicillin

Cross-linking of peptidoglycan

transpeptidase

C NH CH CH C

O

O C N CH

CH3

CH3

COOH

S

STRUCTURE OF PENICILLIN

Antibiotics: Mechanisms of Action

Inhibition of Bacterial Protein Synthesis

- some antibiotics bind to the large or small subunit of the bacterial ribosome

Examples: neomycin, streptomycin, azithromycin, erythromycin, tetracycline

Binding and altering ribosome structure

Aminoglycosides

neomycin

Mechanism of Action

• Once inside the cell…– Bind 30S ribosomal

subunit– Blocks binding of

aminoacyl-tRNA to acceptor site on mRNA-ribosome complex

– Protein synthesis is inhibited = bacteriostatic effect

Summary of Targets

How Antibiotic Resistance Happens

Overcoming the arsenal

• Modify antibiotic

• Pump it out

• Alter the target site

• Bypass the pathway

C NH CH CH C

O

O C N CH

CH3

CH3

COOH

S

Site of penicillinase action.Breakage of the B-lactam ring.

Alter the drug to render ineffective

ex: anti-streptomycin

ex. anti-sulfanilamides

ex: anti-B-lactams

ex: anti-tetracyclins quinolines

Mechanisms of antibiotic resistance

•Efflux Pumps•Hydrolysis•Reduced Uptake•Sequestering•Enzymatic Modification

mechanismsThe four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of ß-lactamases.Alteration of target site: e.g. alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria.Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.[4]There are three known mechanisms of fluoroquinolone resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.[5]

Tetracyclines

• Broad-spectrum activity– Includes aerobic G+ and

G-, atypicals [Rickettsia spp, treponema spp, chlamydia spp, and others]

– Little to no effect on fungi or viruses

• Tetracycline• Doxycycline*• Minocycline• Tigecycline

www.3dchem.com

Summary

• Bacteria have evolved ways to counteract the effects of most antibiotics.

• They mutate to alter target sites or recruit enzymes to degrade or pump out antibiotics

• They share their tricks with other bacteria through gene transfer