ANTIMICROBIAL AGENTS I. INTRODUCTION A. DEFINITIONS B ...

I. INTRODUCTION A. DEFINITIONS

ANTIMICROBIAL AGENTS

B. IMPACT OF ANTIMICROBIALS ON HEALTH CARE

C. HISTORY

D. PRODUCTION, ISOLATION, PURIFICATION OF ANTIBIOTICS

E. THERAPY GUIDELINES 1. Antibiotic must reach site of infection 2. Bacteriostatic drug may work if host defenses are adequate 3. Bacteriocidal drug may be needed in medically compromised patients or in severe infections

F. FUTURE

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II. COMMON MECHANISMS OF ACTION OF ANTIMICROBIALS

Basic sites of antibiotic activity Adapted from Murray, Rosenthal, Pfaller. Medical Microbiology, 5th Edition, Elsevier-Mosby 2005.

A. INHIBITORS OF BACTERIAL CELL WALL SYNTHESIS e.g., Penicillins, Cephalosporins, Vancomycin 1. Bacterial cell walls and membranes a) Gram-positive bacteria

b) Characteristics of Gm (+) bacteria 1) less developed biosynthetic capability 2) high internal osmolality 3) relatively simple cell wall

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c) Gram-negative bacteria

d) Characteristics of Gm (-) bacteria 1) highly developed synthetic capacity 2) highly adaptive 3) low osmolality 4) complex 5 layered cell wall; thin peptidoglycan layer 5) penetration of antibiotic is often restricted - porin channels used for transport of hydrophilic molecules including some antibiotics through the outer membrane

2. Basic Building Blocks of Peptidoglycan layer.

CH 2OH O

OH

HO

OH

OPO 3H 2 CH 2 C COOH phospho-enol-pyruvate

UTP

CH 2OH O

O

HO

OH

NHCCH 3 O

CH 3 CH

COOH

NHCCH 3 O

N-acetyl glucosamine "NAG"

N-acetyl muramic acid "NAM"

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3. Biosynthesis of Glycopeptide a) Precursor Formation (in cytoplasm)

UTP + NAG - phosphate

PEP

PP UDP-NAG

(2)

UDP-NAM L-ala

D-glu

L-ala

racemase (1)

UDP-NAM

D-ala synthase

(1)

D-ala-D-ala

L-lys - tripeptide

UDP-NAM pentapeptide ((12((21)) ))iinnhhiiiinnbbhiihttiieebbddiittebbedyyd cfbboyysycfloofcomsyesycrfciloonimneseyrcinine

NH 3 H CCH C OH

O

d-ala

NH 3 H CCH CO

O N

cycloserine

H 3C

O

HC

CH

fosfomycin

PO 3H 2

H 2C C COOH PO 3H 2

phosphoenol pyruvate

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b) Formation of Linear Peptidoglycan (on cytoplasm side of membrane surface)

UDP-NAM pentapeptide

UMP

P-phospholipid (carrier)

(3)

phospholipid-P-P-NAM pentapeptide UDP-NAG UDP

phospholipid -P-P

phospholipid-P-P-NAM-NAG L-ala D-glu

l-lys

phospholipid-P-P-NAM-NAG l-ala D-glu

D-ala D-ala gly-t-RNA

t-RNA

l - l y s ( G l y5) D-ala

(2)

D-ala

cytoplasm

cytoplasmic membrane

NAM-NAG (bound to peptidoglycan acceptor) l-ala D-glu

l-lys

D-ala D-ala

( G l y5)

growing peptidoglycan

(2) inhibited by vancomycin (binds to d-ala-d-ala) (3) inhibited by bacitracin

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