Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics

Abstract

In this paper, 26 natural polymyxin components and a new derivative S were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E, E-Val, A, M, D, and S showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E, M, and S was similar to that of polymyxin E. Compound S, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S could be a new drug candidate.

A Novel Protein Elicitor PeBL2, from Brevibacillus laterosporus A60, Induces Systemic Resistance against Botrytis cinerea in Tobacco Plant

“…For example, an ISR-eliciting Bacillus cereus strain produces dimethyl disulphide (DMDS), which plays a key role in ISR to B. cereus C1 L and suppress plant fungal diseases ( Huang et al, 2012 ). Additionally, Pseudomonas fluorescens SS101 produces massetolide A, which shows defensive capacity against Phytophthora infestans in tomato by eliciting ISR ( Cui et al, 2018 ). Bacillus subtilis S499 produces fengycins and surfactants, which have ISR-eliciting defensive capacity ( Ongena et al, 2007 ).…”

Purification, Characterization and in vitro Evaluation of Polymyxin A From Paenibacillus dendritiformis: An Underexplored Member of the Polymyxin Family

“…The major components of polymyxin B and E are B 1 and B 2 , and E 1 and E 2 respectively. B 1 and E 1 contain 6-methyloctanoic acid while other two contain isooctanoic acid (i.e., 6-methylheptanoic acid) making a difference of 14 Da ( Storm et al, 1977 ; Cui et al, 2018 ). We believed that our compounds P1 and P2 were also two different variants of the same molecule differing at their fatty acid moiety.…”

“…NMR spectra were consistent with polymyxin M or mattacin ( Martin et al, 2003 ). Upon further literature survey, we came across polymyxin A which has the same mass as polymyxin M but differing with stereochemistry of one amino acid, i.e., Dab residue at the 3rd position, polymyxin A has D-Dab while polymyxin M contains L-Dab ( Choi et al, 2009 ; Shaheen et al, 2011 ; Cui et al, 2018 ). To differentiate between polymyxin M and A, we subjected our strain to whole genome sequencing (deposited under GenBank accession number QKVW00000000 ) and the draft genome was uploaded on AntiSMASH to locate the secondary metabolite clusters.…”

“…This explanation also fits well for our compounds since P1 is less hydrophobic than polymyxin E 2 (P1 has one extra threonine in place of leucine in polymyxin E 2 , making P1 more polar than E 2 ). Also, in a recent paper published by one group in China ( Cui et al, 2018 ), authors studied the efficacy and toxicity of different polymyxin molecules and they also observed that polymyxin A was equally efficacious as compared to polymyxin B and E. Polymyxin A showed less toxicity than all polymyxins studied except polymyxin S 2 and D 2 against Vero kidney cell line. Moreover, the main focus of polymyxin toxicity has been its nephrotoxicity or neurotoxicity in that report and previous literature ( Falagas and Kasiakou, 2006 ; Landman et al, 2008 ; Justo and Bosso, 2015 ; Pogue et al, 2017 ).…”

Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria?

“…[39–44] Because the polymyxins are produced by fermentation, their composition and purity varies between manufacturers. [45] A large number of the components have recently been chemically synthesised and compared for in vitro and in vivo efficacy and toxicity; with polymyxin S 2 potentially showing a better profile than B and E.[46]…”