Medical Microbiology

202 3 GeneralBacteriology

anti-infectiveagentsfora“calculatedantibiotictherapy”canbeselected

evenbeforetheresistancetestresultsarein.Suchtherapiestakeintoaccount

thefrequencyofinfectionsbycertainbacterialspecies(pathogenepide-

miology)aswellascurrentresistancelevelsamongthesebacteria(resistance

epidemiology).

ResistanceMechanisms...............................

Inactivatingenzymes.Hydrolysisormodificationofanti-infectiveagents.

&Betalactamases.Hydrolyzethebetalactamringofbetalactamantibiotics

(seeFig.3. 29 ).Over 200 differentbetalactamasesareknown.Acourseclas-

sificationsystemisbasedonthesubstrateprofileinpenicillinasesandcepha-

losporinases.Productionofsomebetalactamasesisinducedbybetalactams

(seep. 1 69),othersareproducedconstitutively(unregulated).

&Aminoglycosidases.Modifyaminoglycosidesbymeansofphosphoryla-

tionandnucleotidylationoffreehydroxylgroups(phosphotransferasesand

nucleotidyltransferases)oracetylationoffreeaminogroups(acetyltrans-

ferases).

&Chloramphenicolacetyltransferases.Modification,byacetylation,of

chloramphenicol.

Resistanttargetmolecules.

&Geneproductswithalowaffinitytoanti-infectiveagentsareproduced

basedonmutationsinnaturalgenes.Example:DNAgyrasesubunitA,resis-

tantto4-quinolones.

&Acquisitionofagenethatcodesforatargetmoleculewithlowaffinityto

anti-infectiveagents.Theresistanceproteinassumesthefunctionofthe

sensitivetargetmolecule.Example:methicillinresistanceinstaphylococci;

acquisitionofthepenicillin-bindingprotein2a,whichisresistanttobeta-

lactamantibioticsandassumesthefunctionofthenaturallysensitivepeni-

cillin-bindingproteins.

&Acquisitionofthegeneforanenzymethataltersthetargetstructureofan

anti-infectiveagenttorenderitresistant.Example:23SrRNAmethylases;

modificationofribosomalRNAtopreventbindingofmacrolideantibiotics

totheribosome.

Permeabilitymechanisms.

&Reducedinflux.Reductionoftransportofanti-infectiveagentsfromout-

sidetoinsidethroughmembranes;rare.

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Kayser, Medical Microbiology © 2005 Thieme