Many antibiotics that were discovered during the “golden age of antibiotic discovery” 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: rifamycins, β-lactam antibiotics, glycopeptides, macrolides, and fluoroquinolones.

More than 60% of clinically available antibiotic classes are not effective against Gram-negative bacteria due to their inability to infiltrate the Gram-negative outer membrane. A part of our semi-synthetic work is also directed at overcoming the intrinsic Gram-negative resistance of those Gram-positive–selective antibiotics such as rifamycins, macrolides, and moenomycin. We tune the physicochemical properties of antibiotics via semi-synthesis to allow the modified analogues to enter Gram-negative bacteria. We also leverage bacterial uptake systems to facilitate antibiotic entry with minimal rational semi-synthetic modification.

2. Development of small molecular antibacterial therapeutics

During the cell wall biosynthesis, bactoprenol pyrophosphate plays a crucial role for the translocation of precursors from cytoplasm to periplasm. Recently discovered molecules like teixobactin, cilagicin, and clovibactin, derived from uncultured bacteria or biosynthetic engineering target cell wall lipid pyrophosphates. While these natural molecules are promising investigational agents, they face challenges such as complexity, stability, high molecular weight, and high production cost. Natural antibiotics targeting bacterial pyrophosphates typically share positively charged amine groups and lipophilicity. Developing a small molecular approach with similar properties that addresses these limitations and targets lipid pyrophosphates would be beneficial. We have been actively working on the development of small molecular therapeutics that target cell wall lipid pyrophosphates.

3. Natural product drug discovery from untapped Indian microbes and Medicinal plants

Natural product antibiotic discovery is another area of our interest. Microbial natural products have long been the foundation of our antibiotic arsenal. Microbes and their secondary metabolite natural products have evolved over the years and their diversity depends on various factors including the microbial environment, ecological/geographical aspects, environmental factors, and others. India has been home to various natural resources for traditional medicine but most of them have not been characterized for their source of bioactivity. We are interested in exploiting untapped microbes of Indian origin that are associated with ayurvedic medicinal plants (plant microbiome), medicinal soils; soils of remote areas, marine samples, and insects (insect microbiome) as a source of novel natural product antibiotics.

Our natural product drug discovery efforts also extend to the discovery of bioactive natural products from Ayurvedic medicinal plants. Ayurveda is a centuries-old medical science that has been practiced in India for several thousand years; however, the chemical constituents of many Ayurvedic plants remain largely unknown. We have been actively working on the bioactivity-guided purification and characterization of Ayurvedic medicinal plants, with a particular focus on the discovery of anti-infective compounds. ​

4. 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.

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.