Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

Abstract

Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells.

Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

“…Our previous investigations involving polymyxin variants containing reductively labile lipids revealed that the incorporation of lipidated d -Cys based building blocks at the N-terminus consistently gave the most active compounds. 26 Also, among the lipids screened in these studies we identified three moieties that were generally associated with potent antibacterial activity: ethylcyclohexyl, isopentyl, and m -chlorobenzyl. In the present study we therefore elected to focus on position 3 analogues wherein the N-terminal moiety was based on d -Cys linked to these three lipids by means of a disulfide bond.…”

“…The requisite d -Cys lipid-disulfide building blocks were prepared as previously reported. 26 Resin cleavage using mildly acidic conditions yielded protected tripeptides 4a–e , 5a–e , and 6a–e in purities suitable for direct use in the subsequent coupling to PMBH(Boc) 3 3 (Scheme 1C). The solution phase coupling was performed using HCTU/HOBt after which the peptides were fully deprotected by treatment with TFA and purified by RP-HPLC to give 7a–e , 8a–e , and 9a–e .…”

“…1B). 26 The rationale for doing so was based upon the hypothesis that such analogues should be unstable in the more highly reducing environment found inside renal proximal tubule cells, 27 thereby degrading to less toxic metabolites analogous to PMBN. Using this approach, we successfully generated a number of novel polymyxins with antibacterial activity on par with polymyxin B and reduced toxicity towards human renal proximal tubular epithelial cells (PTECs).…”

Biohybrid Microswimmers for Antibiotic Drug Delivery Based on a Thiol‐Sensitive Release Platform

“…[15,16] In the latter, disulfide-containing linkers are frequently used in targeted drug delivery, which often involve "traceless" self-immolating linkers to be released by thiols in thiol exchange reactions. [15,16,70,71] In such a system, the linker will neither be remaining on the system nor on the cargo after release. In this study, we designed and engineered C. reinhardtii as a biohybrid microbot for the targeted delivery of vancomycin, based on a self-immolative, thiol-mediated release platform.…”

“…A complementary approach utilizes endogenous stimuli such as the pH value or redox homeostasis [15,16] . In the latter, disulfide‐containing linkers are frequently used in targeted drug delivery, which often involve “traceless” self‐immolating linkers to be released by thiols in thiol exchange reactions [15,16,70,71] . In such a system, the linker will neither be remaining on the system nor on the cargo after release.…”