4th Commonwealth Chemistry Posters

An ultrashort antibacterial lipopeptide acts as an antibiotic adjuvant to combat multi-drug resistant Gram-negative pathogens

Apurva Panjla,^1‡ Grace Kaul,^1,2,3‡ Manjulika Shukla,² Abdul Akhir,² Sarita Tripathi,⁴ Ashish Arora,^3,4 Sidharth Chopra, ^2,3* and Sandeep Verma ^{1,5* ‡}: contributed equally

¹Department of Chemistry, IIT Kanpur, India, ²Division of Molecular Microbiology and Immunology, CSIR-CDRI, Lucknow, India,³AcSIR, Ghaziabad, India, ⁴Biochemistry and Structural Biology Division, CSIR-CDRI, Lucknow, ⁵Mehta Family Center for Engineering in Medicine, Center for Nanoscience, IIT Kanpur, India.

Problem Statement

»Antimicrobial Resistance (AMR) is the ability of microorganisms to resist the action of antimicrobials.

»It threatens the safety and efficacy of common surgical procedures and immunosuppressive chemotherapy.¹

»WHO declared AMR among TOP 10 GLOBAL HEALTH THREATS

•The WHO critical priority pathogens include multi-drug resistant (MDR) Gram-negative bacteria (GNBs) Acinetobacter baumannii, Pseudomonas aeruginosa and members of the Enterobacteriaceae family.

•~4.95M deaths were associated with bacterial AMR in 2019²

•By 2050, 10 M lives/year (2M in India alone) & $1014 global GDP is at risk³

»There is dire need of new antibiotics with low propensity of resistance and no cross-resistance with existing members of its class.

What are Ultrashort cationic Lipopeptides (USCLs)?

USCLs: Lipopeptides with ≤7 amino acid residues & fatty acid chain(s)4

»Amphiphilic character due to balance of hydrophobic fatty acid chain & hydrophilic peptide moiety4

»Antimicrobial activity of reported USCLs similar to Antimicrobial peptides (AMPs) & Lipopeptides (LPs) but fewer against GNBs

»In the present study,

Fatty acid conjugated tetrapeptides of chemical formula:

R¹-X-R²

were designed and screened against MDR bacterial pathogens, where,

R¹ ranged from C₈–C₁₆ chain alkyl, X denoted the cationic tetrapeptide and

R² was selected from –COOM and CONH2 where M is H or (C₁-C₆) alkyl.

USCL ‘SVAP9I’ exerts broad-spectrum antibacterial activity

»Among the tested Lipopeptides, SVAP9I most potent, best against E. coli among GNBs with a favourable selectivity index of >25

»Antibacterial activity stemmed from adding alkyl chains in a length-dependent manner to the inert tetrapeptide

»SVAP9I’s antibacterial activity is not chiral specific

‘SVAP9I’ is bactericidal with no detectable resistance generation in E. coli

‘SVAP9I’ targets the dual bacterial membranes of GNBs

‘SVAP9I’ sensitized MDR pathogenic GNBs towards narrow-spectrum antibiotics

‘SVAP9I’ acts as an antibiotic adjuvant to Rifampicin in vivo against MDR A. baumannii infections

Conclusions

»A novel USCL ‘SVAP9I’ was designed and identified:

•Active against MDR & XDR GNBs with no detectable resistance

•Targets bacterial dual membrane barrier

•An excellent antibiotic adjuvant

»SVAP9I has the potential to act as an adjuvant to clinically used antibiotic rifampicin against MDR A. baumannii infections.

Acknowledgements

BEI Resources for clinical isolates of E. coli, ECC and A. baumannii; ATCC for K. pneumoniae and P. aeruginosa

Confocal and Electron Microscopy unit at CSIR-CDRI, Lucknow, India

DST–INSPIRE, Lab members and Support staff

References

1. Cancer and Antimicrobial Resistance Challenges and the Path Forward, IDSA, Schmieder and Edwards, 2012.

2. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022

3. Tackling drug-resistant Infections globally: Final report and recommendations. The Review on Antimicrobial Resistance, 2016

4. Ultrashort cationic lipopeptides–effect of N-terminal amino acid and fatty acid type on antimicrobial activity. Molecules, 2020

4th Commonwealth Chemistry Posters

An ultrashort antibacterial lipopeptide acts as an antibiotic adjuvant to combat multi-drug resistant Gram-negative pathogens

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