@article {1858, title = {Azaindole Based Potentiator of Antibiotics against Gram-Negative Bacteria [C-CAMP Startup Bugworks]}, journal = {ACS Infectious Diseases}, year = {2021}, month = {10/2021}, type = {Journal Article}, abstract = {
We discovered azaindole-based compounds with weak innate activity that exhibit substantial potentiation of antibacterial activities of different antibiotics, viz., rifampicin, erythromycin, solithromycin, and novobiocin in Gram-negative bacteria. In the presence of the azaindole derivatives, these antibiotics exhibited submicromolar minimum inhibitory concentrations (MICs) against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The fold improvements in MIC of these antibiotics that were otherwise weak or inactive on their own against these bacteria were also observed against drug-resistant clinical isolates. Our studies indicate that this selective potentiation is probably through destabilization of the outer membrane{\textquoteright}s integrity, known to be regulated by the lipopolysaccharides (LPS). Thus, the azaindole based compounds described here open opportunities for those antibiotics that are otherwise ineffective due to LPS mediated entry barriers in Gram-negative bacteria.
}, keywords = {Azaindole, Bacterial Permeability, Lipopolysachhardies (LPS), Polymyxin, Synergy}, doi = {10.1021/acsinfecdis.1c00171}, url = {https://pubs.acs.org/doi/abs/10.1021/acsinfecdis.1c00171$\#$}, author = {Sharma, Sreevalli and Rao, Ranga and Reeve, Stephanie M and Phelps, Gregory A and Bharatham, Nagakumar and Katagihallimath, Nainesh and Ramachandran, Vasanthi and Raveendran, Savitha and Sarma, Maitrayee and Nath, Anubha} } @article {1861, title = {Structure and function relationship of OqxB efflux pump from Klebsiella pneumoniae [Bugworks, a C-CAMP startup]}, journal = {Nature communications}, volume = {12}, year = {2021}, month = {09/2021}, pages = {1{\textendash}12}, type = {Journal Article}, abstract = {

OqxB is an RND (Resistance-Nodulation-Division) efflux pump that has emerged as a factor contributing to the antibiotic resistance in Klebsiella pneumoniae. OqxB underwent horizontal gene transfer and is now seen in other Gram-negative bacterial pathogens including Escherichia coli, Enterobacter cloacae and Salmonella spp., further disseminating multi-drug resistance. In this study, we describe crystal structure of OqxB with n-dodecyl-β-D-maltoside (DDM) molecules bound in its substrate-binding pocket, at 1.85 {\r A} resolution. We utilize this structure in computational studies to predict the key amino acids contributing to the efflux of fluoroquinolones by OqxB, distinct from analogous residues in related transporters AcrB and MexB. Finally, our complementation assays with mutated OqxB and minimum inhibitory concentration (MIC) experiments with clinical isolates of E. coli provide further evidence that the predicted structural features are indeed involved in ciprofloxacin efflux.

}, doi = {https://doi.org/10.1038/s41467-021-25679-0}, url = {https://www.nature.com/articles/s41467-021-25679-0}, author = {Bharatham, Nagakumar and Bhowmik, Purnendu and Aoki, Maho and Okada, Ui and Sharma, Sreevalli and Yamashita, Eiki and Shanbhag, Anirudh P and Rajagopal, Sreenath and Thomas, Teby and Sarma, Maitrayee and others} } @article {764, title = {Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy [Bugworks Res. Pvt. Ltd., a C-CAMP Startup]}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 May 08}, pages = {7263}, abstract = {

The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression. Using structure-based design, the compounds were optimised to lose their binding to the efflux pump, thereby making them potent on wild-type bacteria. We discovered these compounds to be pro-drugs that require activation in E. coli by specific bacterial nitroreductases NfsA and NfsB. Hit to lead chemistry led to the generation of compounds that were potent on wild-type and multi-drug resistant clinical isolates of E. coli, Shigella spp., and Salmonella spp. These compounds are bactericidal and efficacious in a mouse thigh infection model.

}, issn = {2045-2322}, doi = {10.1038/s41598-018-25407-7}, author = {Hameed P, Shahul and Bharatham, Nagakumar and Katagihallimath, Nainesh and Sharma, Sreevalli and Nandishaiah, Radha and Shanbhag, Anirudh P and Thomas, Teby and Narjari, Riya and Sarma, Maitrayee and Bhowmik, Purnendu and Amar, Prakruthi and Ravishankar, Rajani and Jayaraman, Ramesh and Muthan, Kubendran and Subbiah, Ramesh and Ramachandran, Vasanthi and Balasubramanian, V and Datta, Santanu} }