Identification of structurally diverse menaquinone-binding antibiotics with in vivo activity against multidrug-resistant pathogens

被引:37
作者
Li, Lei [1 ]
Koirala, Bimal [1 ]
Hernandez, Yozen [1 ]
MacIntyre, Logan W. [1 ]
Ternei, Melinda A. [1 ]
Russo, Riccardo [2 ]
Brady, Sean F. [1 ]
机构
[1] Rockefeller Univ, Lab Genet Encoded Small Mol, 1230 York Ave, New York, NY 10021 USA
[2] Rutgers State Univ, New Jersey Med Sch, Ctr Emerging & Reemerging Pathogens, Dept Med, Newark, NJ USA
基金
美国国家卫生研究院;
关键词
MYCOBACTERIUM-TUBERCULOSIS; BIOSYNTHETIC DIVERSITY; STAPHYLOCOCCUS-AUREUS; SP-NOV; DISCOVERY; GENE; WAP-8294A2; PEPTIDES; PIPELINE; BACTERIA;
D O I
10.1038/s41564-021-01013-8
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
(Meta)genomic mining, bioinformatic prediction and chemical synthesis reveal biosynthetic gene clusters encoding structurally new menaquinone-binding antibiotics that are active against multidrug-resistant Staphylococcus aureus in vivo and Mycobacterium tuberculosis in vitro. The emergence of multidrug-resistant bacteria poses a threat to global health and necessitates the development of additional in vivo active antibiotics with diverse modes of action. Directly targeting menaquinone (MK), which plays an important role in bacterial electron transport, is an appealing, yet underexplored, mode of action due to a dearth of MK-binding molecules. Here we combine sequence-based metagenomic mining with a motif search of bioinformatically predicted natural product structures to identify six biosynthetic gene clusters that we predicted encode MK-binding antibiotics (MBAs). Their predicted products (MBA1-6) were rapidly accessed using a synthetic bioinformatic natural product approach, which relies on bioinformatic structure prediction followed by chemical synthesis. Among these six structurally diverse MBAs, four make up two new MBA structural families. The most potent member of each new family (MBA3, MBA6) proved effective at treating methicillin-resistant Staphylococcus aureus infection in a murine peritonitis-sepsis model. The only conserved feature present in all MBAs is the sequence 'GXLXXXW', which we propose represents a minimum MK-binding motif. Notably, we found that a subset of MBAs were active against Mycobacterium tuberculosis both in vitro and in macrophages. Our findings suggest that naturally occurring MBAs are a structurally diverse and untapped class of mechanistically interesting, in vivo active antibiotics.
引用
收藏
页码:120 / +
页数:23
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