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. 2016 Feb 11;59(3):1068-77.
doi: 10.1021/acs.jmedchem.5b01593. Epub 2016 Jan 27.

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

Alejandra Gallardo-Godoy  1 , Craig Muldoon  1 , Bernd Becker  1 , Alysha G Elliott  1 , Lawrence H Lash  2 , Johnny X Huang  1 , Mark S Butler  1 , Ruby Pelingon  1 , Angela M Kavanagh  1 , Soumya Ramu  1 , Wanida Phetsang  1 , Mark A T Blaskovich  1 , Matthew A Cooper  1
Affiliations

Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B

Alejandra Gallardo-Godoy et al. J Med Chem. .

Abstract

The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity-toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure-activity and structure-toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of polymyxin B 1 and polymyxin E (colistin) 2.
Scheme 1
Scheme 1. General On-Resin Cyclization Synthetic Route Exemplified by Synthesis of 10
Reagent and conditions: (i) Cs2CO3, MeOH, H2O, pH 7-8; (ii) allyl bromide, dry DMF; (iii) DHP polystyrene resin, PPTS, dry DCE; (iv) 30% piperidine, DMF; (v) solid-phase peptide synthesis (SPPS) with corresponding amino acid (Table S3), HCTU, DIPEA; (vi) acetic anhydride, pyridine; (vii) Pd(PPh3), PhSiH3; (viii) DPPA, DIPEA, DMF; (ix) 4-Ph-PhCO2H, HCTU, DIPEA; (x) TFA/Et3SiH/H2O (95:1:4).
Scheme 2
Scheme 2. General On-Resin Cyclization Synthetic Route with Selective Dab Modification Used for Synthesis of Compounds 18, 19, 22, 23, 31, and 32
Reagent and conditions: (iv) 30% piperidine, DMF; (v) solid-phase peptide synthesis (SPPS) with corresponding amino acid (Table S3), HCTU, DIPEA; (vi) acetic anhydride, pyridine; (vii) Pd(PPh3), PhSiH3; (viii) DPPA, DIPEA, DMF; (ix) n-C7CO, HCTU, DIPEA; (x) 2% H2NNH2 in DMF; (xi) peptide coupling with corresponding amino acid: Boc-l-Arg(Pbf)-OH or Boc-l-Glu(OtBu)-OH, HCTU, DIPEA; (xii) TFA/Et3SiH/H2O (95:1:4).
Figure 2
Figure 2
In vitro nephrotoxicity studies measuring LDH (A) and GGT (B) release from primary human kidney cells using lead compounds (10, 14, 15, and 38) compared to control compounds (colistin, polymyxin B, and gentamicin).
See this image and copyright information in PMC

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