Teixobactin: A Paving Stone toward a New Class of Antibiotics?

Abstract

Antimicrobial resistance is a serious threat to human health worldwide, prompting research efforts on a massive scale in search of novel antibiotics to fill an urgent need for a remedy. Teixobactin, a macrocyclic depsipeptide natural product, isolated from uncultured bacteria (Eleftheria terrae), displayed potent activity against several Gram-positive pathogenic bacteria. The distinct pharmacological profile and interesting structural features of teixobactin with nonstandard amino acid (three d-amino acids and l-allo-enduracididine) residues attracted several research groups to work on this target molecule in search of novel antibiotics with new mechanism. Herein, we present a comprehensive and critical perspective on immense possibilities offered by teixobactin in the domain of drug discovery. Efforts made by various research groups since its isolation are discussed, highlighting the molecule’s considerable potential with special emphasis on replacement of amino acids. Critical analysis of synthetic efforts, SAR studies, and the way forward are provided hereunder.

Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides

“…This depsipeptide showed excellent activity against Gram-positive bacteria; no mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin were obtained [126]. Unlike other antibiotics, Teixobactin is a cell wall inhibitor that binds lipid II and III instead of proteins; therefore, the development of resistance by mutations of the target should be minimal, which may pave the road toward developing novel antibiotics that avoid the development of resistance [127,128].…”

Into the Unknown: Microbial Communities in Caves, Their Role, and Potential Use

“…More and more strains are reported to display resistance to many antibiotics at once [87]. Therefore, alternative methods of treatment against bacterial infections are being developed, as well as new antimicrobial compounds are being researched [88,89]. Extreme environments such as caves, glaciers, or deep seas seem to be promising sources of microorganisms with properties that could be implemented in medicine [31,90].…”

Escaping mechanisms of ESKAPE pathogens from antibiotics and their targeting by natural compounds

“…In the initial approaches of preparation of teixobactin analogs, L-allo-enduracididine was replaced with various acidic, basic, and neutral amino acids followed by evaluation of their antibacterial potency against MRSA 87 , 88 , 89 . The analogs in which L-allo-enduracididine is substituted with Ile, Leu, Val, and Met were found to have equal or higher antibacterial efficacy than teixobactin suggesting that L-allo-enduracididine is not critical for the antibacterial activity of teixobactin [ 90 , 91 ]. The replacement of N-Me-D-Phe with N-benzyl, N-decyl, N, N-dodecyl, N-decanoyl, N-morpholine, and tetramethyl-N-guanidinylated groups resulted in inactive compounds [92] .…”

“…Recently, Gunjal et al. comprehensively reviewed different aspects of teixobactin including its antibiotic potential, the effect of replacement of amino acids on antibacterial activity, synthetic efforts for its preparation, and structural-activity-relationships [90] . Unconventionally and unlike other antibiotics, teixobactin targets lipids for bactericidal activity (rather than proteins) which minimizes the risk of development of drug resistance by mutations of drug targets.…”