RESUMEN
There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.
Asunto(s)
Antibacterianos , Diseño de Fármacos , Péptidos Cíclicos , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Pruebas de Sensibilidad Microbiana , Depsipéptidos/farmacología , Depsipéptidos/química , Lipoproteínas/química , Lipoproteínas/metabolismo , Lipoproteínas/farmacología , Lipoproteínas/antagonistas & inhibidores , Proteínas Bacterianas , Péptidos , Ácido Aspártico EndopeptidasasRESUMEN
Brevicidine and laterocidine are macrocyclic lipodepsipeptides with selective activity against Gram-negative bacteria, including colistin-resistant strains. Previously, the macrocyclic core of these peptides was thought essential for antibacterial activity. In this study, we show that C-terminal amidation of linear brevicidine and laterocidine scaffolds, and substitution of the native Thr9, yields linear analogues that retain the potent antibacterial activity and low hemolysis of the parent compounds. Furthermore, an alanine scan of both peptides revealed that the aromatic and basic amino acids within the common central scaffold are essential for antibacterial activity. This linearization strategy for modification of cyclic peptides is a highly effective way to reduce the time and cost of peptide synthesis and may be applicable to other non-ribosomal antibacterial peptides.
Asunto(s)
Antibacterianos , Lipopéptidos , Lipopéptidos/química , Antibacterianos/química , Péptidos Cíclicos/química , Bacterias Gramnegativas , Técnicas de Química Sintética , Pruebas de Sensibilidad MicrobianaRESUMEN
The brevicidine and laterocidine family of lipopeptide antibiotics exhibit strong activity against multidrug-resistant Gram-negative bacteria, while showing low propensity to induce resistance. Both peptides feature a branched lipid tail on the N-terminal residue, which for brevicidine is chiral. Here, we report the synthesis and biological evaluation of a library of brevicidine and laterocidine analogues wherein the N-terminal lipid is replaced with linear achiral fatty acids. Optimal lipid chain lengths were determined and new analogues with strong activity against colistin-resistant E. coli produced.
RESUMEN
Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models.
RESUMEN
Tridecaptins are a re-emerging class of non-ribosomal antibacterial peptides (NRAPs) with potent activity against highly problematic strains of Gram-negative bacteria. An intricate mode of action has been reported to explain the bactericidal activity of these NRAPs, wherein they bind selectivity to the Gram-negative version of the peptidoglycan precursor lipid II on the outer leaflet of the inner membrane and disrupt the proton-motive force. Tridecaptins are highly amenable to synthetic modification owing to their linear structure, therefore, various synthetic analogues have been reported, several of which have enhanced antimicrobial activity, reduced cost of synthesis and/or improved stability towards d-peptidase mediated hydrolysis. It has also been demonstrated that unacylated tridecaptins can act synergistically with clinically relevant antibiotics by sensitizing the outer membrane. This review will summarize past literature on the development/discovery of novel tridecaptin analogues (up until the end of 2020), some of which may be useful therapeutic agents to treat insidious Gram-negative bacterial infections.
RESUMEN
Antimicrobial peptides are a rich source of potential antibiotic candidates. The tridecaptins, a family of linear lipo-tridecapeptides, are easily synthesized and show strong activity against Gram-negative bacteria. However, their composition includes several expensive amino acids, such as d/l diaminobutyric acid and d-allo-isoleucine, significantly increasing their cost of synthesis. Herein, we report a series of new tridecaptin derivatives that are much cheaper to synthesize and retain strong activity against multidrug-resistant Gram-negative bacteria.
RESUMEN
d-Stereoselective peptidases that degrade nonribosomal peptides (NRPs) were recently discovered and could have serious implications for the future of NRPs as antibiotics. Herein, we report chemical modifications that can be used to impart resistance to the d-peptidases BogQ and TriF. New tridecaptin A analogues were synthesized that retain strong antimicrobial activity and have significantly enhanced d-peptidase stability. In vitro assays confirmed that synthetic analogues retain the ability to bind to their cellular receptor, peptidoglycan intermediate lipid II.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Péptido Hidrolasas/metabolismo , Péptidos/química , Péptidos/metabolismo , Antibacterianos/metabolismo , Cisteína/química , Estabilidad de Enzimas , Escherichia coli/efectos de los fármacos , Hidrólisis , Pruebas de Sensibilidad Microbiana , Péptido Hidrolasas/química , Péptidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Uridina Difosfato Ácido N-Acetilmurámico/análogos & derivados , Uridina Difosfato Ácido N-Acetilmurámico/metabolismoRESUMEN
Non-ribosomal peptides (NRPs) are a rich source of antibiotic candidates. However, it was recently discovered that resistance to NRPs can be mediated by d-stereoselective peptidases. The tridecaptins, a class of NRPs that selectively target Gram-negative bacteria, are degraded by the d-peptidase TriF. Through analysis of a solution NMR structure of tridecaptin A1, we have rationally synthesized new cyclic tridecaptin analogues that retain strong antimicrobial activity and are resistant to TriF.