In-silico modeling of a novel OXA-51 from β-lactam-resistant Acinetobacter baumannii and its interaction with various antibiotics

Tiwari, Vishvanath; Nagpal, Isha; Subbarao, Naidu; Moganty, Rajeswari R.

doi:10.1007/s00894-011-1346-3

Cited by 35 publications

(25 citation statements)

References 32 publications

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“…The crystal structure for an OXA-51-like enzyme has not been solved, but structural modeling and sequence analysis can be used to identify structural elements involved in activity toward the carbapenems. A recent study that conducted in silico docking of ␤-lactam substrates into a molecular model of OXA-51 showed that imipenem had the weakest interaction with the enzyme, with ceftazidime showing the strongest interaction (47). However, these data are inconsistent with kinetic data where hydrolysis of ceftazidime was not detected (45,46).…”

Section: Oxa-51-like ␤-Lactamasesmentioning

confidence: 99%

OXA β-Lactamases

2014

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SUMMARY The OXA β-lactamases were among the earliest β-lactamases detected; however, these molecular class D β-lactamases were originally relatively rare and always plasmid mediated. They had a substrate profile limited to the penicillins, but some became able to confer resistance to cephalosporins. From the 1980s onwards, isolates of Acinetobacter baumannii that were resistant to the carbapenems emerged, manifested by plasmid-encoded β-lactamases (OXA-23, OXA-40, and OXA-58) categorized as OXA enzymes because of their sequence similarity to earlier OXA β-lactamases. It was soon found that every A. baumannii strain possessed a chromosomally encoded OXA β-lactamase (OXA-51-like), some of which could confer resistance to carbapenems when the genetic environment around the gene promoted its expression. Similarly, Acinetobacter species closely related to A. baumannii also possessed their own chromosomally encoded OXA β-lactamases; some could be transferred to A. baumannii , and they formed the basis of transferable carbapenem resistance in this species. In some cases, the carbapenem-resistant OXA β-lactamases (OXA-48) have migrated into the Enterobacteriaceae and are becoming a significant cause of carbapenem resistance. The emergence of OXA enzymes that can confer resistance to carbapenems, particularly in A. baumannii , has transformed these β-lactamases from a minor hindrance into a major problem set to demote the clinical efficacy of the carbapenems.

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Section: Oxa-51-like ␤-Lactamasesmentioning

confidence: 99%

OXA β-Lactamases

2014

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“…(www.schrodinger.com 2008). The general method followed for ligand docking in flexible mode was described in detail in our earlier protocol (Tiwari et al, 2012c). However, a brief description of various steps is given below:…”

Section: Docking Using Grid Based Ligand Docking Using Energeticsmentioning

confidence: 99%

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

Tiwari

Moganty

2013

Journal of Biomolecular Structure and Dynamics

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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.

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“…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).…”

Section: Quantitative Proteomics As a Tool To Study Of Carbapenem Resmentioning

confidence: 99%

Quantitative proteomics to study carbapenem resistance in Acinetobacter baumannii

Tiwari

2014

Front. Microbiol.

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Acinetobacter baumannii is an opportunistic pathogen causing pneumonia, respiratory infections and urinary tract infections. The prevalence of this lethal pathogen increases gradually in the clinical setup where it can grow on artificial surfaces, utilize ethanol as a carbon source. Moreover it resists desiccation. Carbapenems, a β-lactam, are the most commonly prescribed drugs against A. baumannii. Resistance against carbapenem has emerged in Acinetobacter baumannii which can create significant health problems and is responsible for high morbidity and mortality. With the development of quantitative proteomics, a considerable progress has been made in the study of carbapenem resistance of Acinetobacter baumannii. Recent updates showed that quantitative proteomics has now emerged as an important tool to understand the carbapenem resistance mechanism in Acinetobacter baumannii. Present review also highlights the complementary nature of different quantitative proteomic methods used to study carbapenem resistance and suggests to combine multiple proteomic methods for understanding the response to antibiotics by Acinetobacter baumannii.

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In-silico modeling of a novel OXA-51 from β-lactam-resistant Acinetobacter baumannii and its interaction with various antibiotics

Cited by 35 publications

References 32 publications

OXA β-Lactamases

OXA β-Lactamases

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

Quantitative proteomics to study carbapenem resistance in Acinetobacter baumannii

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