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Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.

ABSTRACT: The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.

SUBMITTER: Blaskovich MAT

PROVIDER: S-EPMC5750218 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.

Blaskovich Mark A T MAT Hansford Karl A KA Gong Yujing Y Butler Mark S MS Muldoon Craig C Huang Johnny X JX Ramu Soumya S Silva Alberto B AB Cheng Mu M Kavanagh Angela M AM Ziora Zyta Z Premraj Rajaratnam R Lindahl Fredrik F Bradford Tanya A TA Lee June C JC Karoli Tomislav T Pelingon Ruby R Edwards David J DJ Amado Maite M Elliott Alysha G AG Phetsang Wanida W Daud Noor Huda NH Deecke Johan E JE Sidjabat Hanna E HE Ramaologa Sefetogi S Zuegg Johannes J Betley Jason R JR Beevers Andrew P G APG Smith Richard A G RAG Roberts Jason A JA Paterson David L DL Cooper Matthew A MA

Nature communications 20180102 1

The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively ...[more]

PMID: 29295973

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Project description:Daptomycin is a last resort antibiotic for the treatment of infections caused by many Gram-positive bacterial strains, including vancomycin-resistant Enterococcus (VRE) and methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). However, the emergence of daptomycin-resistant strains of S. aureus and Enterococcus in recent years has renewed interest in synthesizing daptomycin analogs to overcome resistance mechanisms. Within this context, three aromatic prenyltransferases have been shown to accept daptomycin as a substrate, and the resulting prenylated analog was shown to be more potent against Gram-positive strains than the parent compound. Consequently, utilizing prenyltransferases to derivatize daptomycin offered an attractive alternative to traditional synthetic approaches, especially given the molecule's structural complexity. Herein, we report exploiting the ability of prenyltransferase CdpNPT to synthesize alkyl-diversified daptomycin analogs in combination with a library of synthetic non-native alkyl-pyrophosphates. The results revealed that CdpNPT can transfer a variety of alkyl groups onto daptomycin's tryptophan residue using the corresponding alkyl-pyrophosphates, while subsequent scaled-up reactions suggested that the enzyme can alkylate the N1, C2, C5, and C6 positions of the indole ring. In vitro antibacterial activity assays using 16 daptomycin analogs revealed that some of the analogs displayed 2-80-fold improvements in potency against MRSA, VRE, and daptomycin-resistant strains of S. aureus and Enterococcus faecalis. Thus, along with the new potent analogs, these findings have established that the regio-chemistry of alkyl substitution on the tryptophan residue can modulate daptomycin's potency. With additional protein engineering to improve the regio-selectivity, the described method has the potential to become a powerful tool for diversifying complex indole-containing molecules. KEY POINTS: • CdpNPT displays impressive donor promiscuity with daptomycin as the acceptor. • CdpNPT catalyzes N1-, C2-, C5-, and C6-alkylation on daptomycin's tryptophan residue. • Differential alkylation of daptomycin's tryptophan residue modulates its activity.

Dataset Information

Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.

Publications

Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.

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