Molecular Bacteriology and Chemical Genetics Group

Current research areas

Small RNAs with big jobs

Acinetobacter baumannii is a nosocomial pathogen known to cause pneumonia, soft tissue, wound, and urinary tract infections. It is considered scorch in healthcare settings due to its multidrug-resistant (MDR) phenotype and various virulence traits, causing a high mortality and morbidity rate worldwide. One key aspect that makes A. baumannii a successful pathogen is its ability to survive in harsh conditions within the host and its environment. Such pathophysiological prowess is conferred by small regulatory RNA (sRNA) mediated Post-transcriptional regulation. RNA chaperones, like Hfq and their cognate sRNA-mRNA binding partners, mediate such responses. Our studies in A. baumannii have led to identifying 31 putative sRNAs in this pathogen. These sRNAs are small 50-300 nucleotide long RNA molecules that bind and regulate a plethora of mRNA targets. We found that one such putative target of an sRNA of A. baumannii encodes an efflux pump that imparts resistance against fosfomycin. We further elucidated the role of the unusually long Hfq molecule in A. baumannii and found it to be critical in imparting physiological fitness in this bacterium. Through our fundamental apporaches we established that the glycine repeats on the C-terminal domain of A. baumannii Hfq exhibit evolutionary conservation and confer pathophysiological fitness to this pathogen. Our findings imply that Hfq and the pathways kept under regulation by its cognate sRNA partners are potential drug targets and will help combat MDR A. baumannii in the future.

New Drugs for Bad Bugs

The emergence of antibiotic drug resistance has become a global health concern. Despite various efforts in combating the problem, the antibiotic pipeline remains under a dry spell for over 50 years. The Pathania research group aims to discover novel small molecules with antibacterial potential in the wake of antimicrobial resistance. Our group utilizes chemical genetics approaches for the discovery of novel antibacterials that target key metabolic pathways in ESKAPE pathogens. With the help of high-throughput screening of small molecule libraries, we have discovered multiple antibacterial and adjunct molecules. After the screening of a small-molecule library of 10,956 molecules, we identified IITR06144 among 29 other potential antibacterial leads. IITR06144 belongs to the nitrofuran class and exhibits broad-spectrum bactericidal activity against most MDR bacteria and nitrofurantoin-resistant clinical isolates. Additionally, it exhibits anti-persister and anti-biofilm activity.

Rescuing the rescuers

Carbapenemases are the enzymes that confer the ability to resist the antibacterial action of carbapenems, the last resort beta-lactam antibiotics. Since the scattered earlier reports on the identification of carbapenemases, these enzymes now have been isolated from all over the world and need immediate attention. Overall we aim to develop inhibitors against carbapenemases OXA-48, KPC-2 and NDM-1 that revive the activity of carbapenems against the pathogens expressing these carbapenemases. The potential leads are validated by biophysical and structural characterization (Structure-Activity Relationship, SAR) and the best compounds are evaluated for their preclinical potential by studying their in-vivo safety and efficacy in mice. As a combined Indo-Norway effort we have developed a lead series of KPC-2 and OXA-48 inhibitors. Recently, we identified a US-FDA approved drug that is used for the treatment of alcoholism as an NDM-1 inhibitor and showed that it reduces bacterial burden in mice with pneumonia and systemic infection.

Molecular Wingmen

Efflux pumps are the part of the bacterial membrane of nearly all bacteria that expel out lipophilic or amphipathic molecules. Overexpression of these pumps results in antibiotic resistance by lowering their effective cellular concentration. Our research group is involved in the characterization of new efflux pumps, their regulatory mechanisms, effect on bacterial biology, and their role in virulence. We discovered a new efflux pump AbaF in Acinetobacter baumannii, that is associated with intrinsic fosfomycin resistance. We also screen novel small molecule inhibitors for efflux utilizing chemical genetics approach. Recently, a small molecule IITR08027 was fished out of a small molecule library and which restores the antibacterial activity of the fluoroquinolones class of antibiotics against multidrug-resistant Acinetobacter baumannii by efflux inhibition. Another molecule, a bi-functional chalcone IMRG4 was discovered that inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of the fluoroquinolone Norfloxacin.

Antibiotic resistance in the environment

Antibiotics are not only the gold standard for human healthcare, but they are also widely employed in livestock and aquaculture. However, it may target normal microbial flora that plays a major role in global biogeochemical cycles when released into the environment, thereby affecting ecological sustainability. The excessive accumulation of antibiotics in the environment also eventually increases the antibiotic-resistance gene pool in the environment. Humans' high anthropogenic activities also change the local climate, which perturbs interactions between species and forces species to adapt, migrate, and be replaced by others or go extinct. Temperature is significantly related to bacterial survival, reproduction, and other activities such as pathogenesis. The increase of horizontal gene transfer among the bacteria is affected by temperature, a leading source of the evolution of multidrug-resistant bacteria. Therefore, we simulate the climatic conditions and investigate the effect of temperature on antibiotic resistome and bacterial diversity in the environmental samples.

Funding Agencies

DBT/Wellcome Trust India Alliance

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