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Resistance
Interruption or disturbance
one or more the steps essential
for effective antimicrobial action
Partial or complete
loss of antibiotic effectiveness
Genetic basis of resistance
• Intrinsic resistance
– natural resistance possessed by most strains of a
bacterial species
• Mutational / acquired resistance
– Due to mutation affecting genes : deletion,
substiution, addition
Examples of Intrinsic Resistance to Antimicrobial Agent
Forbes R Betty et al. Bailey & Scott’s Diagnostic Microbiology. 12th Ed. 2007
Intrinsic Resistance Can be caused by :
1. Impermeability
• Lack of affinity of the drug for the bacterial target
2. Biofilm
• Inaccessibility of the drug into the bacterial cell
3. Efflux
• Extrusion of the drug by chromosomally encoded efflux pumps
4. Enzymatic Inactivation
• Innate production of enzymes that inactive the drug
Transferable Resistance
Target Site Modification
1. Chromosomal Mutation
QUINOLONE
– Quinolon target DNA gyrase & Topoisomerase IV
inhibiting DNA synthesis
– Plasmid mediated quinolone resistance gene qnr
mutation encoding amino acid changes in the
genes encoding DNA Topoisomerase
– Quinolone resistance-determining region (QRDR)
gyrA & gyrB subunit
– In Gram-positive bacteria : 1st step mutation leading
to fluoroquinolone resistance parC or parE subunit
topoisomerase IV ; 2nd step gyrA
Target Site Modification
2. Enzymatic Target Site Alteration
Enzymatic alteration reduced affinity of
antibiotics
Macrolides
– Resistance mediated by Erythromycin ribosome
methylase (ERM) found on plasmids and Tns
allow broad dissemination to many bacterial
species
Cont.
Macrolides
– Cross resistance : macrolide-lincosamide-
streptogramin B (MLSB)
Vancomycin
– Resistance encoded by vanA & vanB genes
Acquisition of new target
• By acquiring cellular targets with reduced affinity
for the antibiotic.
– S. aureus evaded the antimicrobial activity of
methicillin by acquiring a mobile element carrying a
staphylococcal casette chromosome mec (SCCmec)
confers resistance to methicilin
Mobile DNA element encodes a triad of genes :
mecR1-mecI-mecA
mecA gene responsible for methicilin resistance &
encodes a new PBP, PBP2A (also PBP2A’)
Acquisition of new target (cont.)