Structural studies on New Delhi Metallo-β-lactamase (NDM-2) suggest old β-lactam, penicillin to be better antibiotic for NDM-2-harbouringAcinetobacter baumanni

Abstract

Acinetobacter baumannii, a Gram-negative pathogen causes nosocomial infections including pneumonia, urinary tract and respiratory infections. Carbapenem group of β-lactam antibiotics are routinely used to treat A. baumannii including multidrug-resistant clinical strains. The emergence of New Delhi Metallo-β-lactamase (NDM-2), a new type of β-lactamase and one of the major resistant determinants in A. baumannii, opened up challenges in the treatment of resistant strains. Thus, understanding the structure-function relationship of NDM-2 with different analogues of β-lactams becomes crucial. We carried out in silico studies on the interaction of various β-lactams with NDM-2 and with OXA-24, a carbapenem hydrolyzing non-NDM type β-lactamase. The binding affinity of the β-lactams to NDM-2 was found to be in the order: ceftazidime ≈ imipenem ≈ 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 β-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.

Comparative mechanism based study on disinfectants against multidrug‐resistant Acinetobacter baumannii

“…[4][5][6][7][8][9][10][11][12][13][14] Hospital-acquired infections are associated with high mortality and morbidity rates 15,16 ; hence, their prevention and cure are urgently needed. [4][5][6][7][8][9][10][11][12][13][14] Hospital-acquired infections are associated with high mortality and morbidity rates 15,16 ; hence, their prevention and cure are urgently needed.…”

Significances of OMV and Extracellular Vesicle Proteomics

“…Proteomic study of outer membrane of the E. coli revealed over expression FhuE and FhuA, and YbiL that have role in the iron transport [119]. By differential proteomics study, the role of iron in the continued existence of A. baumannii resistance strain (ATCC and carbapenem) in human host is revealed [120,121]. Proteome of the human host changes during Acinetobacter baumannii infection.…”

Quantitative proteomics to study carbapenem resistance in Acinetobacter baumannii

“…Role of proteins detected by the quantitative proteomics methods has been validated by other in-vitro or in-vivo methods. It was found that Acinetobacter baumannii develop resistance against carbapenem via alteration in the expression/activity of β-lactamase (Tiwari et al, 2012a,b,c; Tiwari, 2013, 2014; Tiwari and Moganty, 2013, 2014) and alteration in the penicillin binding protein (Vashist et al, 2011). Upregulation of metabolic enzymes/proteins found in the inner membrane protein also enhanced the carbapenem resistance in A. baumannii (Tiwari et al, 2012c).…”