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Synthesis, biological evaluation and membranotropic properties of quinoline-antimicrobial peptide conjugates as antibacterial drugs
Pierre Laumaillé * 1 , Alexandra Dassonville-Klimpt 1 , Sophie Da Nascimento 1 , Catherine Mullié 1 , François Peltier 1, 2 , Claire Andréjak 1, 3 , Sandrine Castelain 1, 2 , Sandrine Morandat 4 , Karim El Kirat 4 , Pascal Sonnet 1
1  AGIR, EA 4294, UFR of Pharmacy, Jules Verne University of Picardie, 80037 Amiens, France;
2  Department of Bacteriology, Amiens University Hospital, 80054 Amiens, France
3  Respiratory and Intensive Care Unit, Amiens University Hospital, 80054 Amiens, France
4  Laboratory of Biomechanics and Bioengineering, UMR CNRS 7338, Compiègne University of Technology (UTC), 60205 Compiègne, France

Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5
10.3390/ECMC2019-06320
Abstract:

Tuberculosis and nosocomial infections are among the most frequent causes of death in the world. Mycobacteria such as Mycobacterium tuberculosis and ESKAPE bacteria are pathogens particularly implicated in these infectious diseases1. The lack of antibiotics with novel mode of action associated with the spread of drug resistant bacteria make the fight against these infections particularly challenging.

Using antimicrobial peptides (AMPs) to restore or to broaden antibacterial activity of antibiotics is an interesting strategy to fight resistant strains. For example, the conjugation between chloramphenicol and ubiquicidine29-41 gives a conjugate with increased activity against Escherichia coli and reduced toxicity against neutrophils compared to chloramphenicol alone 2.

During previous work on the development of new anti-infective drugs, we identified a series of quinolines active against Gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecalis. Concerning Gram-negative bacteria, some of them were active on E.coli but not against Pseudomonas aeruginosa3,4. In order to broaden the antibacterial spectrum of this heterocycle core, we synthesized quinoline-based conjugates with short AMP sequences5. Their antibacterial activities against a panel of bacteria and mycobacteria will be discussed. Membranotropic properties study through tensiometry measures on bacterial mimetic membrane models was carried out to elucidate their mechanism of action.

References:

  1. (a) WHO, Global tuberculosis report 2017; (b) Khan, H. A., Baig, F. K. & Mehboob. Nosocomial infections: Epidemiology, prevention, control and surveillance, Asian Pac. J. Trop. Biomed. 2017, 7, 478–482.
  2. (a) Arnusch et al. Enhanced Membrane Pore Formation through High-Affinity Targeted Antimicrobial Peptides. PLoS ONE 2012 7:e39768; (b) Chen et al. Bacteria-Targeting Conjugates Based on Antimicrobial Peptide for Bacteria Diagnosis and Therapy. Mol. Pharm. 2015, 12, 2505.
  3. Jonet, A.; Dassonville-Klimpt, A.; Sonnet, P.; Mullié, C. Side chain length is more important than stereochemistry in the antibacterial activity of enantiomerically pure 4-aminoalcohol quinoline derivatives. J. Antibiot. (Tokyo) 2013, 66, 683–686.
  4. Laumaillé, Dassonville-Klimpt, Peltier, Mullié, Andréjak, Da-Nascimento, Castelain, Sonnet, Synthesis and study of new quinolineaminoethanols as anti-bacterial drugs, Pharmaceuticals 2019, 12(2), 91.
  5. Strøm, M. B. et al. The Pharmacophore of Short Cationic Antibacterial Peptides, 2003, 46, 3–6.

Keywords: Quinoline; AMP; AMP conjugates; antibacterial drugs; membranotropic properties
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