Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 31, Issue 6, Pages 591-601Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2012.706075
Keywords
New Delhi Metallo--Lactamase; NDM; NDM-2; Acinetobacter baumannii; Carbapenem resistance; Penicillin; OXA-24
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Funding
- Council of Scientific and Industrial Research, India [09/006(0361)/2006-EMR-1]
- Indian Council of Medical Research, New Delhi [ICMR-5/3/3/18/2009-ECD-I]
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Acinetobacter baumannii, a Gram-negative pathogen causes nosocomial infections including pneumonia, urinary tract and respiratory infections. Carbapenem group of -lactam antibiotics are routinely used to treat A. baumannii including multidrug-resistant clinical strains. The emergence of New Delhi Metallo--lactamase (NDM-2), a new type of -lactamase and one of the major resistant determinants in A. baumannii, opened up challenges in the treatment of resistant strains. Thus, understanding the structurefunction relationship of NDM-2 with different analogues of -lactams becomes crucial. We carried out in silico studies on the interaction of various -lactams with NDM-2 and with OXA-24, a carbapenem hydrolyzing non-NDM type -lactamase. The binding affinity of the -lactams to NDM-2 was found to be in the order: ceftazidime approximate to imipenem approximate to doripenem>oxacillin>aztreonam>penicillin; however, the order of their affinity to OXA-24 was quite different: ceftazidime>aztreonam>penicillin>oxacillin>doripenem>imipenem. Further, NDM-2 in comparison to OXA-24 showed stronger interaction (less X-score) with most of the -lactams except penicillin. This suggests higher lethality posed by clinical strains expressing NDM-2 than those without NDM-2. Weak interaction between NDM-2 and penicillin clearly points out that penicillin is perhaps better option in treating A. baumannii harbouring NDM-2. Present findings provide new insights in drug resistance at the molecular level of NDM-2 and can help in designing structure-based drugs.
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