Tridecaptin M, a New Variant Discovered in Mud Bacterium, Shows Activity against Colistin- and Extremely Drug-Resistant Enterobacteriaceae

Abstract

The World Health Organization has categorized the Gram-negative superbugs, which are inherently impervious to many antibiotics, as critical priority pathogens due to the lack of effective treatments. The breach in our last-resort antibiotic (i.e., colistin) by extensively drug-resistant and pan-drug-resistant Enterobacteriaceae strains demands the immediate development of new therapies. In the present study, we report the discovery of tridecaptin M, a new addition to the family, and its potential against colistin-resistant Enterobacteriaceae in vitro and in vivo. Also, we performed mode-of-action studies using various fluorescent probes and studied the hemolytic activity and mammalian cytotoxicity in two cell lines. Tridecaptin M displayed strong antibacterial activity (MICs of 2 to 8 μg ml−1) against clinical strains of Klebsiella pneumoniae (which were resistant to colistin, carbapenems, third- and fourth-generation cephalosporins, fluoroquinolones, fosfomycin, and other antibiotics) and mcr-1-positive Escherichia coli strains. Unlike polymyxins, tridecaptin M did not permeabilize the outer membrane or cytoplasmic membrane. It blocked ATP synthesis in bacteria by dissipating the proton motive force. The compound exhibited negligible acquired resistance, low in vitro cytotoxicity and hemolytic activity, and no significant acute toxicity in mice. It also showed promising efficacy in a thigh infection model of colistin-resistant K. pneumoniae. Altogether, these results demonstrate the future prospects of this class of antibiotics to address the unmet medical need to circumvent colistin resistance in extensively drug-resistant Enterobacteriaceae infections. The work also emphasizes the importance of natural products in our shrunken drug discovery pipeline.

Lipid-Based Antimicrobial Delivery-Systems for the Treatment of Bacterial Infections

“…Secondly, rampant overuse of antibiotics has yielded, and still is yielding new antibiotic-resistant strains that cannot be killed by known antibiotics (Neville and Jia, 2019). Thirdly, development of new antibiotics is stalling (N'Guessan et al, 2018;Jangra et al, 2019), because their effective lifetime before the first resistant strains arise, is becoming shorter and shorter, decreasing the incentive for commercialization and therewith clinical use of new antibiotics (Liu et al, 2019b).…”

Bombyx mori gloverin A2 alleviates enterotoxigenic Escherichia coli-induced inflammation and intestinal mucosa disruption

“…Especially, they exhibit activity against some antibiotics-resistant bacterial species. For instance, the tridecaptin M was found to exhibit activity against many colistin-resistant E. coli strains in vitro and in vivo [15]. Importantly, a number of studies have shown that AMPs plays a critical role in immune regulation [16,17].…”

In Vitro Evaluation of Antimicrobial Peptide Tridecaptin M in Combination with Other Antibiotics against Multidrug Resistant Acinetobacter baumannii

“…Tridecaptins are a class of lipopeptide antibiotics that retain activity against multidrug-resistant Gram-negative bacteria. The main members of this class include tridecaptin A [ 35 ], tridecaptin B [ 36 ], and tridecaptin M [ 37 ]. Recently, unacylated tridecaptin A 1 (without the lipid moiety; Figure 1 ), though ineffective itself, was reported to potentiate (or reduce the minimum inhibitory concentration of) Gram-positive antibiotics in Gram-negative bacteria including Enterobacteriaceae and A. baumannii [ 38 ].…”

“…Recently, unacylated tridecaptin A 1 (without the lipid moiety; Figure 1 ), though ineffective itself, was reported to potentiate (or reduce the minimum inhibitory concentration of) Gram-positive antibiotics in Gram-negative bacteria including Enterobacteriaceae and A. baumannii [ 38 ]. Tridecaptins have very low intrinsic activity against A. baumannii [ 36 , 37 ], but they could still permeabilize the outer membrane very efficiently [ 39 ]. The naturally occurring tridecaptins are active against Enterobacteriaceae but have not been investigated for their potential in combination therapy.…”