Resistance Mechanisms

Inactivating enzymes. Hydrolysis or modification of antiinfective agents.

& Betalactamases. Hydrolyze the betalactam ring of betalactam

antibiotics (see Fig. 3.29). Over 200 different betalactamases

are known. A course classification system is based on the
substrate

profile

in

penicillinases

and

cephalosporinases.

Production of some betalactamases is induced by betalactams

(see p. 169), others are produced constitutively (unregulated).
& Aminoglycosidases. Modify aminoglycosides by means of

phosphorylation and nucleotidylation of free hydroxyl groups

(phosphotransferases

and

nucleotidyl

transferases)

or

acetylation of free amino groups (acetyltransferases).

&

Chloramphenicol

acetylation, of
chloramphenicol.

acetyltransferases.

Modification,

by

Resistant target molecules.

& Gene products with a low affinity to anti-infective agents are

produced
based on mutations in natural genes. Example: DNA gyrase
subunit A, resistant to 4-quinolones.
& Acquisition of a gene that codes for a target molecule with

low affinity to anti-infective agents. The resistance protein

assumes

the

function

of

the

sensitive

target

molecule.

Example: methicillin resistance in staphylococci; acquisition of

the

penicillin-binding

protein

2a,

which

is

resistant

to

betalactam antibiotics and assumes the function of the

naturally sensitive penicillin- binding proteins.
& Acquisition of the gene for an enzyme that alters the target

structure of an anti-infective agent to render it resistant.

Example: 23S rRNA methylases;
modification of ribosomal RNA to prevent binding of macrolide
antibiotics
to the ribosome.

Permeability mechanisms.
& Reduced influx. Reduction of transport of anti-infective agents

from outside to inside through membranes; rare.

& Increased efflux. Active transport of anti-infective agents

from inside to outside by means of efflux pumps in the

cytoplasmic membrane, making efflux greater than influx;
frequent.