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Overview of Antibiotic Resistance in Staphylococcus Aureus

One of the most serious challenges to the treatment of hospital-acquired infections is the appearance and spread of methicillin resistant Staphylococcus aureus (MRSA), which carries a mechanism that comprehensively protects the pathogen against the beta-lactam family of antibacterial drugs.

In a recently published expert review, Ian Chopra, PhD., DSc, from University of Leeds, in Leeds, United Kingdom, reviewed the evolution of antibiotic resistance in S. aureus and considered approaches and discoveries that may lead to future treatments.

Methicillin was introduced to counter an increase of S. aureus hospital isolates that expressed resistance to penicillin. The first MRSA strains were reported in 1961, within a year of the introduction of methicillin to clinical practice.

Strains of methicillin-sensitive S. aureus have three penicillin binding proteins that engage in essential cross-link formation between neighbouring UDP-MurNAc-pentapeptide side chains in nascent peptidoglycan. MRSA express an additional PBP (PBP2´) with reduced affinity for beta-lactam antibiotics. While other PBPs in MRSA are inactivated by methicillin, PBP2´ continues to perform cross-linking in the absence of normal PBP activity.

Vancomycin, the current drug of choice for treating MRSA, binds to the UDP-MurNAc-pentapeptide cell wall precursors and prevents the subsequent transglycosylation and transpeptidation steps required for cell wall maturation.

MRSA strains with intermediate susceptibility to vancomycin were first reported in 1996. Although vancomycin resistance is associated with multiple genetic changes, it does not appear to depend on elevated spontaneous mutation rates. Vancomycin is ineffective against MRSA strains that carry the vanA determinant with MIC values in the range of 64 to 1000 mcg/mL.

Linezolid is a new synthetic antibacterial agent approved for treating MRSA related pneumonia, as well as skin and soft tissue infections. It disrupts bacterial growth by inhibiting protein synthesis initiation.

As with methicillin, MRSA resistance to linezolid was reported within 1 year of clinical use. Linezolid resistance is associated with G2576T mutation in all 5 operons encoding 23S rRNA.

The development of new drugs that minimise potential for future resistance is crucial due to the lack of additional treatment options. Dr. Chopra organised avenues for development into four main categories: expansion of known antibiotic classes, discovery of resistance mechanism inhibitors, re-examination of earlier antibiotic classes, and genome-based approaches.

Drugs that provide multiple blockades are desirable, as resistance would depend on mutation in several targets. Success with this approach is most probable in groups of essential bacterial enzymes that are mechanistically related, making it possible to design or screen for a single inhibitor of multiple members of the enzyme class (for example, tRNA synthetases, two component signal transduction systems, and muramyl peptide ligases).

"Although we have not yet addressed the MRSA muramyl peptide ligases, the utility of structure-based inhibitor design for this enzyme class has been demonstrated by our recent success in designing and synthesizing macrocyclic inhibitors of E. coli MurD," Dr. Chopra notes. "Extension of these approaches to the MRSA Mur enzymes will be a worthwhile exercise."
Expert Rev Anti-infective Ther 2003;1:1:45-55. "Antibiotic resistance in Staphylococcus aureus: concerns, causes and cures"

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