You are on page 1of 28

By MSB Imasa

ƒ

Based on acquisition pattern: 
Natural versus Acquired

ƒ

Based on expression of resistance: 
Genotypic vs Phenotypic

Neomycin. Tetracycline. Chloramphenicol.TYPES OF RESISTANCE Based on acquisition pattern ƒ Natural: Intrinsic Resistance  Organisms are resistant to antibiotics derived from them (resistance gene ) Streptomyces species: resistant to Cefoxitin. Streptomycin. Vancomycin  Lack of transporter or antibiotic- binding proteins  Increased efflux activity .

TYPES OF RESISTANCE Based on acquisition pattern ƒ Acquired: Resistance developing among initially antibiotic-sensitive bacteria  Mutations in chromosomal genes  Acquisition of transferrable genetic elements that carry resistance genes (plasmids or transposons) .

antibiotic persisters.TYPES OF RESISTANCE Based on expression of resistance ƒ ƒ Genetic drug resistance: due to chromosomal mutations or acquisition of antibiotic resistance genes on plasmids or transposons Phenotypic drug resistance: due to changes in the bacterial physiological state (stationary phase. dormant state) .

ƒ ƒ Chromosomal mutations Transfer of resistance genes .

GENETIC DRUG RESISTANCE Chromosomal Mutations ƒ 5 General Mechanisms  Reduced permeability  Increased efflux  Enzymatic inactivation  Alteration or over-expression of drug target  Loss of activating enzymes .

ƒ Porins outer membrane proteins allowing entry of hydrophilic antibiotics .

OmpU. OprD ƒ Mutations  OmpF mutations lead to antibiotic resistance of Neisseria gonorrhoea to penicillin and tetracycline Enterobacter aerogenes to cephalosporin  OprD mutations lead to carbapenem resistance .ƒ Porins  Examples: OmpF. OmpC. PORINS Mutations and antibiotic resistance PhoE.

Am J of Med. FC. 2006 .Tenover.

.

Multidrug and toxic compound extrusion (MATE) . ATP binding cassette (ABC) .ƒ Efflux pump families and antibiotic substrates Increased Efflux Mutations and antibiotic resistance Resistance nodulation division (RND). Major facilitator superfamily (MFS). Staphylococcal multiresistance (SMR) .

aeruginosa: confers intrinsic mutliple drug resistance (to tetracycline.Increased Efflux Mutations and antibiotic resistance ƒ ƒ RND family of MDR efflux pumps: confer resistance of gram negative bacteria to Linezolid Presence of MexAB-OprM and MexXY-OprM efflux pumps in wild-type P. and some fluoroquinolones) . chloramphenicol.

LJV. 2006 . Clin Microb Rev.Piddock.

2006 . Clin Microb Rev. LJV.Piddock.

Clin Microb Rev.Piddock. LJV. 2006 .

coli.Increased Efflux Mutations and antibiotic resistance ƒ Most RND MDR efflux pump genes are encoded by operons that are under the control of the local repressor gene usually a TetR-type repressor  AcrA and AcrB are cotranscribed and under the control of acrR in many bacteria Mutations in acrR derepress expression of acrB. aerogenes . influenzae. and acrS represses acrEF giving rise to overexpression of the efflux pump  Explains MDR strains of E. H. enterica serovar Typhimurium. and E. S.

.

ENZYMATIC INACTIVATION Mutations and antibiotic resistance ƒ Enzymatic inactivation Beta-lactamases: cleave beta-lactam antibiotics and cause resistance Aminoglycoside-inactivating enzymes: add Acetyl. and Phosphoryl groups to inactivate the antibiotic Chloramphenicol Acetyl Transferase: inactivates Chloramphenicol Streptogramin Acetyl Transferase: inactivates Streptogramin . Adenyl.

.

tuberculosis PBP (penicillin-binding proteins) alteration: leads to penicillin resistance Muramyl peptide change from D-Ala-D-Ala to D-Ala-D-lactate: leads to vancomycin resistance (vancomycin prevents cross-linking of peptidoglycan by binding to D-Ala-D-Ala dipeptide of the muramyl peptides Mutations in DNA gyrase A and B subunits: leads to quinolone resistance Mutations in rpoB gene encoding beta-subunit of RNA polymerase: leads to Rifampicin resistance ƒ ƒ ƒ ƒ .ALTERED DRUG TARGET Mutations and antibiotic resistance ƒ InhA (-15C to T promoter mutation): mutation causes over-expression of the drug target InhA. and leads to a low-level isoniazid (INH) resistance in M.

ƒ INH requires KatG (catalaseperoxidase) for activation: mutation of KatG leads to INH resistance Metronidazole requires RdxA (nitroreductase) for activation: mutation in RdxA leads to Metronidazole resistance ƒ .

GENETIC DRUG RESISTANCE Transfer of resistance genes ƒ Mechanisms of Genetic Transfer  Conjugation  Transformation  Transduction .

GENETIC TRANSFER Conjugation Plasmid: circular DNA that replicates independent of the chromosome Pilus: bridges two bacteria enabling genetic transfer .

GENETIC TRANSFER Transformation Transformation: transfer of naked DNA containing resistance gene from a dead bacterium to live bacterium .

GENETIC TRANSFER Transduction Bacteriophage virus that infects bacteria and take over genetic activity within bacteria Inadvertent incorporation of some bacterial DNA (resistance gene) to the phage DNA that is transferred to newly infected bacteria .

GENETIC TRANSFER Examples Streptomycin-resistance genes. strAand strB: Streptomycin-resistance genes carried on plasmid ƒ Sulfonamide-insensitive enzyme: carried on plasmids and confer sulfonamide resistance ƒ Plasmid-mediated qnr (quinolone resistance): ƒ  qnr gene encodes a device called pentapeptide. which is a DNA mimic  Pentapeptide binds to the DNA gyrase and competes with the quinolones from binding to the gyrase.  Causes low-level resistance .

ƒ ƒ ƒ Biofilms Salicylate -Induced Antibiotic Resistance Bacterial Persisters .