Natural lipopeptide antibiotic tripropeptin C revitalizes and synergistically potentiates the activity of beta-lactams against methicillin-resistant Staphylococcus aureus

Hashizume, Hidetoshi; Takahashi, Yoshiaki; Harada, S.; Nomoto, Akio

doi:10.1038/ja.2014.169

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…More specifically, TPPC forms a complex with undecaprenyl pyrophosphate in the presence of calcium ions and, thus interfering with the lipid cycle of the cell wall synthesis ( Hashizume et al, 2011 ). It has also been reported that TPPC is able to potentiate and re-sensitise MRSA to beta (β)-lactam antibiotics, further indicating this compound’s promise as an effective antimicrobial agent ( Hashizume et al, 2015 ).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Underexplored bacteria as reservoirs of novel antimicrobial lipopeptides

et al. 2022

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Natural products derived from microorganisms play a prominent role in drug discovery as potential anti-infective agents. Over the past few decades, lipopeptides produced by particularly Bacillus, Pseudomonas, Streptomyces, Paenibacillus, and cyanobacteria species, have been extensively studied for their antimicrobial potential. Subsequently, daptomycin and polymyxin B were approved by the Food and Drug Administration as lipopeptide antibiotics. Recent studies have however, indicated that Serratia, Brevibacillus, and Burkholderia, as well as predatory bacteria such as Myxococcus, Lysobacter, and Cystobacter, hold promise as relatively underexplored sources of novel classes of lipopeptides. This review will thus highlight the structures and the newly discovered scaffolds of lipopeptide families produced by these bacterial genera, with potential antimicrobial activities. Additionally, insight into the mode of action and biosynthesis of these lipopeptides will be provided and the application of a genome mining approach, to ascertain the biosynthetic gene cluster potential of these bacterial genera (genomes available on the National Center for Biotechnology Information) for their future pharmaceutical exploitation, will be discussed.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Underexplored bacteria as reservoirs of novel antimicrobial lipopeptides

et al. 2022

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“…Tripropeptins from Lysobacter sp. strain BMK333-48F3 are another group of cyclic lipodepsipeptides that inhibit the lipid cycle of bacterial cell wall biosynthesis by forming a complex with Ca 2ϩ and undecaprenyl pyrophosphate (11,12). Cephabacins from Lysobacter lactamgenus contain a cephem core attached to an oligopeptide side chain (13)(14)(15).…”

Section: Importancementioning

confidence: 99%

Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes

Han

Wang

et al. 2017

Appl Environ Microbiol

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species are a group of environmental bacteria that are emerging as a new source of antibiotics. One characteristic of is intrinsic resistance to multiple antibiotics, which had not been studied. To understand the resistance mechanism, we tested the effect of blocking two-component regulatory systems (TCSs) on the antibiotic resistance of, a prolific producer of antibiotics. Upon treatment with LED209, an inhibitor of the widespread TCS QseC/QseB, produced a large amount of an unknown metabolite that was barely detectable in the untreated culture. Subsequent structural elucidation by nuclear magnetic resonance (NMR) unexpectedly revealed that the metabolite was indole. Indole production was also markedly induced by adrenaline, a known modulator of QseC/QseB. Next, we identified two TCS genes, () and , in and found that mutations of and also led to a dramatic increase in indole production. We then chemically synthesized a fluorescent indole probe that could label the cells. While the (cytoplasmic response regulator) mutant was clearly labeled by the probe, the (membrane sensor) mutant was not labeled. It was reported previously that indole can enhance antibiotic resistance in bacteria. Therefore, we tested if the dramatic increase in the level of indole production in upon blocking of and would lead to enhanced antibiotic resistance. Surprisingly, we found that indole caused the intrinsically multiantibiotic-resistant bacterium to become susceptible. Point mutations at conserved amino acids in -QseC also led to antibiotic susceptibility. Because indole is known as an interspecies signal, these findings may have implications. The environmental bacterium is a new source of antibiotic compounds and exhibits intrinsic antibiotic resistance. Here, we found that the inactivation of a two-component regulatory system (TCS) by an inhibitor or by gene deletion led to a remarkable increase in the level of production of a metabolite in, and this metabolite was identified to be indole. We chemically synthesized a fluorescent indole probe and found that it could label the wild type and a mutant of the TCS cytoplasmic response regulator but not a mutant of the TCS membrane sensor. Indole treatment caused the intrinsically multidrug-resistant bacterium to be susceptible to antibiotics. Mutations of the TCS sensor also led to antibiotic susceptibility. Because indole is known as an interspecies signal between gut microbiota and mammalian hosts, the observation that indole could render intrinsically resistant susceptible to common antibiotics may have implications.

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“…133 Notably, tripropeptin C not only has potent antibiotic activity but also is able to reverse β-lactam antibiotic resistance in MRSA. 134 The cyclic lipodepsipeptide is able to revitalize and synergistically potentiate the activity of beta-lactams against MRSA. The mechanism of the reversal is tripropeptin C's inhibition of expression of the β-lactam-inducible blaZ and mecA genes, which encode β-lactamase and foreign penicillin-binding protein, respectively.…”

Section: Natural Products From Lysobactermentioning

confidence: 99%