ESKAPE Pathogens.pptx

Mechanism of resistance

1. ESKAPE Pathogens Dr Mayuri Rani

2. What are ESKAPE Pathogens?

3. In February 2017, to focus and guide research and development related to new antibiotics, the WHO published its list of pathogens for which new antimicrobial development is urgently needed.  Within this broad list, ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii , Pseudomonas aeruginosa, and Enterobacter species) pathogens were designated “priority status

4. In February 2017, to focus and guide research and development related to new antibiotics, the WHO published its list of pathogens for which new antimicrobial development is urgently needed.  Within this broad list, ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii , Pseudomonas aeruginosa, and Enterobacter species) pathogens were designated “priority status

5. T hrough genetic mutation and the acquisition of mobile genetic elements (MGEs) ESKAPE pathogens have developed resistance mechanisms against  oxazolidinones,  lipopeptides,  macrolides,  fluoroquinolones,  tetracyclines,  lactams,  lactam–-lactamase inhibitor combinations,   antibiotics that are the last line of defense, ( carbapenems, glycopeptides, and clinically unfavorable polymyxins  Comparatively, resistance to lipoglycopeptides is rare and has only recently been Documented) 

6. ESKAPE PATHOGEN MECHANISMS OF ANTIBIOTIC RESISTANCE

7. Antibiotic Inactivation/Alteration

8. Target Site Modifications

9. Target enzyme modification  Beta Lactam antibiotics inhibit bacteria by binding to PBP enzymes anchored in the cell wall. In MRSA, resistance to methicillin and other Beta lactam antibiotics is mediated through expression of the foreign mecA gene.   MecA codes for PBP2a, a modifed PBP with a low affnity for -lactams, which renders most betalactam agents completely ineffective against MRSA 

10. Ribosomal target site alterations A major mechanism of resistance to macrolide lincosamide -streptogramin B (MLSB) antibiotics in S. aureus and Enterococcus spp. Is mediated by the erm-encoded rRNA methyltransferases. hese enzymes mono- or  dimethylate the A2058 residue within the 23S rRNA of the bacterial 50S ribosomal subunit, thus impairing MLSB target binding (196, 197).  Expression of erm can be either constitutive or inducible. Constitutively expressing strains display cross-resistance to all MLSB agents.  In contrast, inducibly resistant strains show resistance to 14- and 15-member inducer macrolides (e.g., erythromycin, clarithromycin, and azithromycin) but remain susceptible to lincosamides and streptogramin.

11. Cell wall precursor alterations One of the most important AMR mechanisms that has emerged in Gram-positive ESKAPE organisms in recent decades has been the development of glycopeptide resistance.  In susceptible Gram-positive organisms, bacterial cell wall biosynthesis is inhibited by glycopeptides that target outer cell wall D-Ala–D-Ala peptidoglycan precursor residues.  Glycopeptide resistance in enterococci involves the acquisition of van gene clusters which coordinate:  ( i ) the synthesis of modified peptidoglycan precursors that exhibit subdued glycopeptide binding (i.e., the natural D-Ala–D-Ala termini are replaced with either D-Ala-D-lactate or D-Ala–D-serine) and (ii) the production of D,D-carboxypeptidases that eliminate residual natural D-Ala– D-Ala precursors from the host cell.

12. Reduced Antibiotic Penetration and Accumulation

13. Other Mechanisms and Survival Strategies

14. MOBILE GENETIC ELEMENTS CONFERRING ANTIMICROBIAL RESISTANCE