“MBLI” - Development of new approaches to overcome MBL-related resistance in bacteria

06 September 2018

Project coordinator:

Jayanta Haldar

Jawaharlal Nehru Centre for Advanced Scientific Research


Project partners:

Cristiano Marcelo Espinola Carvalho

Dom Bosco Catholic University


Tatiana V. Ovchinnikova

M.M.Shemyakin & Yu.A.Ovchinnikov Institute of Bioorganic Chemistry RAS


Hixen Xie

East China University of Science and Technology


Funding agencies:

CNPq (Brazil), RFBR (Russia), DST (India), NSFC (China)


As the antibiotic pipelines dwindles along with the increase of resistance to antibiotics, it has become necessary to discover new antimicrobials with novel modes of action. β-lactams have been one of the most extensively used antibiotics but bacterial resistance has limited their use in current clinical settings. Although numerous new β-lactams and β-lactamase inhibitors have been developed, bacteria quickly developed mechanisms to render them ineffective. Despite efforts, there is currently no inhibitor for metallo-β-lactamase in the clinical pipeline. All the inhibitors used in the clinics or in the clinical pipeline are inhibit serine- β-lactamases. The project aims to develop new approaches to overcome MBL-related resistance in bacteria. Novel MBL inhibitors that incorporate membrane-disruption properties and Zn-binding properties in order extract or bind to zinc ion in the active site of the MBL will be developed. Antimicrobial peptides (AMPs) are possible alternatives to conventional antibiotics due to their high efficacy against a broad range of MBL-producing pathogens. Recombinant AMP of different structural classes (α-helical, β-sheet, Pro-rich) will also be developed. These antibacterial molecules to be developed are expected to exhibit broad-spectrum activity against both Gram-positive and Gram-negative bacteria either through inherent membrane-disruption property or in combination with other antibiotics. The probability as well as mechanisms of development of bacterial resistance to the molecules developed herein, will be studied. Also, the rapid identification of inhibitor activity relies on an efficient assay platform. Fluorescent substrates, especially carbapenem-specific fluorogenic sensors, unlike traditional colorimetric substrates, are highly sensitive in the detection of metallo-β-lactamases activities, allowing high throughput screening of inhibitors.  In order to achieve this, a highly sensitive fluorescent-based assay platform will be set up.