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Drugs to combat antimicrobial resistance

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Prof. Tandon’s laboratory is first to identify, evaluate, and establish benzimidazoles as the selective inhibitors bacterial topoisomerase I relative to mammalian topoisomerase in vitro, suggesting that topoisomerase poisoning underlies the antibacterial effects. The substituted benzimidazoles selectively poison bacterial cellular processes while allowing mammalian cells to perform typically. This is in principle, of considerable interest as very few specific inhibitors of topoisomerase I are known to date. Interestingly, these molecules do not act on DNA gyrase and do not inhibit human topoisomerase also. The idea is to identify a novel antibacterial agent that can fight bacterial resistance and not host.

In continuing our interest in drug development, she identified a new antimicrobials class to combat bacterial resistance to the existing antibiotics. Our group showed 5-(4- Propylpiperazin-1-yl)-2-[2′-(4-ethoxyphenyl)-5′-benzimidazolyl] benz-imidazole (PPEF) as selective bacterial topoisomerase I & III inhibitor, but do not effect human topoisomerase and gyrases. The compound showed a bactericidal effect in several gram-positive and negative pathogenic MDR clinical strains. Computational studies delineated PPEF interacts in the vicinity of the acidic triad of topoisomerase IA and do not allow religation of DNA strands. The upregulation of efflux genes and down regulation of porins were observed in PPEF treated bacterial cells. Ligand-induced chromosome condensation, generation of focal points, cell filamentation in bacterial cells confirmed the bactericidal nature of PPEF in pathogenic MDR strains. Further, she studied the compound’s efficacy in Balb/C mice, immunocompromised mice and observed significant bacterial load reduction for both gram-negative E. coli and positive S. aureus MDR strains. It is safe and offers good bioavailability in mice.

Our group has completed screening of PPEF and BPVF against 640 multi-drug resistant pathogenic strains of eleven gram-negative and positive bacterial strains (A. baumannii, Enterobacteriaceae spp. E. faecium, S. aureus, Salmonellae, S. pneumonia, Shigella spp) & E.coli (ESBL producing Strain). These bacteria were identified by WHO as “Priority Pathogens” in the year 2017-18. She has established collaboration with academia, clinicians, and industries. DBT-BIRAC has sanctioned a collaborative project involving two institutions and Anthem Biosciences, Bangalore (CRO), to collect all GLP and GMP laboratory data on antibacterial agents to move to India’s Drug Controller for IND approvals, clinical trials.

The development of antimicrobial resistance by bacterial strains is a serious and growing threat worldwide. Comprehensive knowledge on the burden and associated outcomes of multi-drug resistant (MDR) infections is still lacking. It prompted the WHO in 2017 to publish it’s first-ever list of antibiotic-resistant “priority pathogens “(critical, high, and medium priority), underscoring 12 bacterial species for research and development of new antibiotics. In 2019 WHO released the report, drug-resistant diseases could cause 10 million deaths each year by 2050. To address this problem is to continuously synthesize new antibiotics against defined targets, which may or might lead to resistance within month or so by different pathogenic strains. Therefore to address this problem, discovery of a new target to combat antimicrobial resistance could possibly give a solution or extend the lifetime of newly synthesized future antibiotics.

Combating the rising tide of antibiotic resistance requires expeditious development of neoteric therapeutic agents with unique scaffolds to counter new targets in the pathogenic bacteria. Research efforts over the past few years have focused on the development of novel classes of antibacterial with the twin objectives of avoiding cross-resistance and reducing the emergence of de novo resistance. Topoisomerases are the enzyme that controls the topology of the DNA and play an important role in various cellular vital processes like replication, transcription, and repair pathways. Type IA topoisomerases introduces single DNA strand break and does not require ATP for its activity and present in all three domain of life. Our lab has synthesized different analogue of bisbenzimidazoles (JAC 2012, JMC 2014), 2-(3,4-dimethoxyphenyl)-5-(5-(4 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidazole (DMA) and 2′-(4-ethoxyphenyl)-5-(4-propylpiperazin-1-yl)-1H,1’H-2,5′-bibenzo(d]imidazole (PPEF) are found as a potent EcTopo IA inhibitors. PPEF and BPVF showed strong antibacterial activity against ~75 bacterial strains of 08 WHO identified dreaded pathogens and it was observed that PPEF binds at the acidic triad of the catalytic domain of EcTopo IA (BBA 2019) which prevents the stabilization of DNA and magnesium ion to the DDE motif.

Docked pose of the ternary complex of PPEF with E. coli topoisomerase-IA-dsDNA. (A) Docked structure of 12b with EcTopo 1A-dsDNA, (B) Inset docked pose showing interaction of 12b with Glu9, Pro11, Glu313, Arg321, and His365; all the structures are colored by element,and relevant structures are labeled. Dotted lines indicated interaction between 12b and residues, whereas arrows indicate hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) sites.

Further potency or efficacy of the molecules was established via In vivo studies using nuteropenic thigh infection and septicaemia mice model (Sci Rep 2017).

References :

  1. Nimesh, H., Sur, S., Sinha, D., Yadav, P., Anand, P., Bajaj, P., Virdi, J. and Tandon, V., 2014. Synthesis and Biological Evaluation of Novel Bisbenzimidazoles as Escherichia coli Topoisomerase IA Inhibitors and Potential Antibacterial Agents. Journal of Medicinal Chemistry, 57(12), pp.5238-5257.
  2. Bansal, S., Sinha, D., Singh, M., Cheng, B., Tse-Dinh, Y. and Tandon, V., 2012. 3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I. Journal of Antimicrobial Chemotherapy, 67(12), pp.2882-2891.
  3. Bansal, S., Sinha, D., Singh, M., Cheng, B., Tse-Dinh, Y. and Tandon, V., 2012. 3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I. Journal of Antimicrobial Chemotherapy, 67(12), pp.2882-2891.
  4. Sinha, D., Pandey, S., Singh, R., Tiwari, V., Sad, K. and Tandon, V., 2017. Synergistic efficacy of Bisbenzimidazole and Carbonyl Cyanide 3-Chlorophenylhydrazone combination against MDR bacterial strains. Scientific Reports, 7(1).