2. Academic Validation
  3. Azaindole Based Potentiator of Antibiotics against Gram-Negative Bacteria

Azaindole Based Potentiator of Antibiotics against Gram-Negative Bacteria

  • ACS Infect Dis. 2021 Nov 12;7(11):3009-3024. doi: 10.1021/acsinfecdis.1c00171.
Sreevalli Sharma 1 2,  Ranga Rao 1 2,  Stephanie M Reeve 3,  Gregory A Phelps 3 4,  Nagakumar Bharatham 1 2,  Nainesh Katagihallimath 1 2,  Vasanthi Ramachandran 1 2,  Savitha Raveendran 1,  Maitrayee Sarma 1,  Anubha Nath 5,  Teby Thomas 5,  Dhanasekaran Manickam 6,  Savitha Nagaraj 7,  V Balasubramanian 1,  Richard E Lee 3,  Shahul Hameed P 1 2,  Santanu Datta 1
Affiliations

Affiliations

  • 1 BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, GKVK, Bellary Rd, Bangalore, Karnataka 560065, India.
  • 2 The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bengaluru, Karnataka-560064, India.
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4 Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5 St. John's Research Institute, Bengaluru, Karnataka-560034, India.
  • 6 Syngene International Ltd., Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India.
  • 7 St. John's Medical Hospital, Bengaluru, Karnataka-560034, India.
PMID: 34699190 DOI: 10.1021/acsinfecdis.1c00171
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'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; Lipopolysaccharides (LPS); Synergy; polymyxin.

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