RESEARCH INTERESTS

Bacterial antimicrobial resistance (AMR), a slow-moving/silent pandemic, has emerged as one of the leading global public health threats in the 21st century. According to the ICMR report, AMR is rising in India in common pathogens as exemplified by the appearance of extensively drug-resistant Mycobacterium tuberculosis (Mtb) and multidrug-resistant Gram-negative bacterial pathogens. Therefore, this ever-increasing AMR calls for continuous efforts for the discovery and development of novel durable antimicrobials. Based on the molecular mechanisms of drug resistance, the mode of antibiotic action, and pathogen-host interactions; we are currently working on various molecular therapeutic designs to combat bacterial infections.

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1. Development of durable antimicrobial drugs

The antibiotics that were discovered in the 20th century have now become obsolete due to the emergence of AMR. We are interested in incorporating additional modes of antibiotic actions to these existing antibiotics by means of peripheral semi-synthetic chemical modifications. Thus, if bacteria were to develop resistance to one mode of action still the other modes would work. Further, bacteria would be futile in acquiring resistance to such dual or multi-pronged antibiotics and such compounds are expected to be durable. We are currently working on the semi-synthetic developments of the following classes of antibiotics to install additional modes of action: tetracyclines, rifamycins, penicillins, macrolides, fluoroquinolones, etc.

 

2. Natural product drug discovery

The majority of natural product antibiotics were discovered from soil actinomycetes during the golden age of antibiotic discovery (1930s – 1970s). However, contemporary studies in identifying new antibiotics from soil isolates mainly resulted in no success due to the frequent rediscovery of known compounds. Our research group is interested in identifying bioactive natural product producers beyond actinomycetes especially our focus would be towards non-pathogenic Gram-negative bacteria. Untapped microorganisms of Indian origin that are associated with ayurvedic medicine are also of interest to us in order to isolate bioactive natural products. Our natural product drug discovery platform is not only focused on antibacterials, but also on other drug discovery areas such as anticancer agents, antivirals, antimalarials, and antifungals.

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3. Antibiotic adjuvants

Antibiotic adjuvants are non-antibiotic compounds that enhance antibiotic activity either by blocking resistance (Class I agents) or by boosting the host response to infection (Class II agents). Antibiotic adjuvants offer an orthogonal and complementary strategy to new antibiotic discovery. These compounds can enhance and preserve the activity of our existing drug arsenal. The most clinically successful adjuvants are the inhibitors of β-lactamases, enzymes that hydrolytically inactivate β-lactam antibiotics.

 

a) Resistance inhibitors

Resistance to antibiotics occurs through a variety of molecular mechanisms, including decreased drug permeability, active efflux, alteration or bypass of the drug target, production of antibiotic-modifying enzymes. All of these mechanisms are susceptible to inhibition by small molecules, making them potential targets for antibiotic adjuvants. We are interested in identifying compounds that block common resistance elements found in both Gram-positive and Gram-negative bacteria.

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b) Host-directed therapy

Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence. For example, in the case of pulmonary tuberculosis, host matrix metalloproteases aid the pathogen in spreading the infection. We are interested in targeting such host cell factors with our chemical designs.

 

4. Anti-virulence strategies

Anti-virulence therapy, rather than killing the pathogens, attempts to deprive their virulence factors and thus augurs well in conjunction with antibiotic treatment. Pathogens use virulence factors (biomolecules and structures) to colonise, invade, and persist in a susceptible host. Bacterial toxins (invasion) and biofilms (colonise and persist) are responsible for the majority of bacterial virulence. Biofilms, symbiotic communities of surface-associated microbial cells encased in an extracellular polymeric substance matrix, are resistant to the action of antimicrobial drugs. We are interested in developing molecular designs that neutralize bacterial exotoxins and agents that act against bacterial biofilms.

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