Mechanism of Antimicrobial

Resistance

Ni Nyoman Sri Budayanti

 Learning task
• What is antimicrobial resistance
• Why antibacterial resistance is a concern
• How does antibacterial work
• Explain about intrinsic resistance, acquired
resistance and transfer of material genetic
• How does mechanism of antibacterial resistance
• Explain about the causes of antibiotic resistance
 Definition of antibiotic
 An antibiotic is a substance produced by
various species of living microorganisms (e.g.
bacteria and fungi)
• Inhibit pathogens by interfering with
intracellular processes
 Term antibiotic includes synthetic
antimicrobial agents i.e. sulphonamides
 Antibiotics do not kill viruses -not effective in
treating viral infections.
• Antimicrobial resistance (AMR) is the ability of
microorganisms that cause disease to
withstand attack by antimicrobial medicines
• The ability of pathogens that works against
the antibiotics is termed Antibiotic Resistance
• Antimicrobial resistance (AMR) :
– Increasing worldwide,
– reducing the efficacy of therapy,
– fuelling transmission of pathogen,
– majoring health cost, morbidity & mortality
• Natural mutation: 1 mutant in 106-109 bacteria
• Increasing mutants  induced by antibiotic
irrational used
Mims Cedric, et al. Medical Microbiology. 3rd Ed. 2004
 Target sites for antibiotic action
• Inhibitor of bacterial cell wall synthesis
• Inhibitor of bacterial protein synthesis
• Inhibitor of nucleic acid synthesis
• Affecting membrane permeability
Bacterial Cell Wall

Bauman RW. 2015. Microbiology with disease by body system

Principles of Antibiotic 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.)

– Sulfonamide : the sulI & sulII wich encodes drug-

resistant dihydropteroate synthases (in Gram-
negative)
 Enzymatic Inactivation of Antibiotic

• β-lactamase selectively hydrolyze to inactive

penicilloic acid.
• β – lactamase classified into 4 major groups :
– Class A, C, D  act by serine mechanism
– Class B  require Zinc (metallo based enzymes)
• Currently > 1000 β-lactam resistance genes
have been identified