In vitro and in silico screening of Klebsiella pneumoniae new Delhi metallo-β-lactamase-1 inhibitors from endophytic Streptomyces spp.

Abstract

The increase in drug resistance over the last two decades is a big threat in health care settings. More importantly, the dissemination of carbapenem-resistant Enterobacteriaceae is the major threat to public health with an increase in morbidity and mortality. β-lactamase is known to confer enteric bacteria with nearly complete resistance to all β-lactam antibiotics including the late-generation carbapenems. The commercially available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam are being met with an increasing number of resistant phenotypes and are ineffective against pathogens harbouring New Delhi metallo-β-lactamase (NDM-1). Inhibition of New Delhi metallo-β-lactamase-1 activity is one potential way to treat metallo β-lactamase (MBL) producing multi drug resistant (MDR) pathogen. The present study focused on screening of Klebsiella pneumoniae New Delhi metallo-β-lactamase-1 (BLIs) from endophytic Streptomyces spp. using in vitro and in silico methods. The study identified three potential inhibitors of New Delhi metallo-β-lactamase-1, namely dodecanoic acid, dl-alanyl-l-leucine and phenyl propanedioic acid. These molecules were found to bind to other MBLs namely, IMP-1 and VIM-2. To the best of our knowledge, this is the first kind of study reporting the binding mode of these molecules with New Delhi metallo-β-lactamase-1.

Communicated by Ramaswamy H. Sarma

Keywords:

• β-lactamase inhibitors
• Streptomyces spp.
• drug resistance
• molecular interactions

Acknowledgements

The authors acknowledge infrastructural support through the SERB, DST for financial support for funding this research and the DBT grant (BT/PR23795/BID/7/797/2017) to carry out computational studies and SASTRA Deemed to be University for Schrodinger software (https://www.schrodinger.com/) support.

Additional information

Funding

Science and Engineering Research Board (SERB), Department of Science and Technology, New Delhi (EMR/2016/007613) to JP. DBT grant (BT/PR23795/BID/7/797/2017) Junior Research Fellowship for AD.