Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

Abstract

Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made.

New polymyxin derivatives that display improved efficacy in animal infection models as compared to polymyxin B and colistin

“…In a neutropenic mouse lung infection model with P. aeruginosa and A. baumannii , CA824 was unequivocally more effective on a weight basis than polymyxin B . In the mouse thigh infection model with A. baumannii , CA824 was as effective as polymyxin B, despite its higher MIC in vitro …”

“…The majority of these compounds possessed four to five positive charges and several analogues had d ‐Ser, Dap, or d ‐Dap at position R3. Out of these analogues, the properties of CA824 have thus far been published in more details . Against E. coli , K. pneumoniae , and P. aeruginosa , the modal MIC values were similar to those of polymyxin B, but against A. baumannii , the MICs were fourfold higher.…”

“…In cytotoxicity assays using HK‐2 cell cultures, CA824 was significantly less cytotoxic (half‐maximal inhibitory concentration [IC 50 ], 148 μg/mL) than polymyxin B (IC 50 , 15 μg/mL) …”

“…General interest in developing novel and improved polymyxins has grown considerably during the last years, as reviewed by Vaara, Vaara et al., Velkov et al., Pirri et al., Kadar et al., and Cochrane et al., as well as very recently (2017) by Brown and Dawson and Rabanal and Cajal . This review focuses on describing novel derivatives that have been shown to be more effective than the old polymyxins in animal infection models.…”

Linear Thanatin Is an Effective Antimicrobial Peptide against Colistin-Resistant <i>Escherichia coli in Vitro</i>

“…The polymyxins including Polymyxin B and colistin (polymyxin E) have been used as Gram-negative therapeutics since their discovery in late 1940s [3] [4]. Today, colistin has become the last line drug for MDR Gram-negative bacteria infections [5].…”