Synthesis and antibacterial activity of tripropeptin C derivatives modified at the carboxyl groups

Hirosawa, Sehei; Takahashi, Yoshiaki; Hashizume, Hidetoshi; Miyake, T.; Akamatsu, Yuzuru

doi:10.1038/ja.2013.128

Cited by 10 publications

(8 citation statements)

References 13 publications

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“…[21], we found a match with a BGC in the genome of the beta-proteobacterium Collimonas fungivorans Ter33 ( Figure S1 ). The tripropeptins are highly important molecules from a pharmaceutical point of view, as tripropeptin B and C display potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae [22], [23]. All in all, the results of the NORINE searches show how even in the absence of new peptidogenomic data Pep2Path can identify putative genomic loci that encode the biosynthesis of important molecules, opening up new possibilities to further engineer these pathways and/or produce the compounds in high titers through metabolic engineering or heterologous expression.…”

Section: Resultsmentioning

confidence: 99%

Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products

et al. 2014

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Nonribosomally and ribosomally synthesized bioactive peptides constitute a source of molecules of great biomedical importance, including antibiotics such as penicillin, immunosuppressants such as cyclosporine, and cytostatics such as bleomycin. Recently, an innovative mass-spectrometry-based strategy, peptidogenomics, has been pioneered to effectively mine microbial strains for novel peptidic metabolites. Even though mass-spectrometric peptide detection can be performed quite fast, true high-throughput natural product discovery approaches have still been limited by the inability to rapidly match the identified tandem mass spectra to the gene clusters responsible for the biosynthesis of the corresponding compounds. With Pep2Path, we introduce a software package to fully automate the peptidogenomics approach through the rapid Bayesian probabilistic matching of mass spectra to their corresponding biosynthetic gene clusters. Detailed benchmarking of the method shows that the approach is powerful enough to correctly identify gene clusters even in data sets that consist of hundreds of genomes, which also makes it possible to match compounds from unsequenced organisms to closely related biosynthetic gene clusters in other genomes. Applying Pep2Path to a data set of compounds without known biosynthesis routes, we were able to identify candidate gene clusters for the biosynthesis of five important compounds. Notably, one of these clusters was detected in a genome from a different subphylum of Proteobacteria than that in which the molecule had first been identified. All in all, our approach paves the way towards high-throughput discovery of novel peptidic natural products. Pep2Path is freely available from http://pep2path.sourceforge.net/, implemented in Python, licensed under the GNU General Public License v3 and supported on MS Windows, Linux and Mac OS X.

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Section: Resultsmentioning

confidence: 99%

Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products

et al. 2014

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“…6 BM-TPPC was synthesized as reported previously. 11 We purchased Penicillin G, ampicillin, amoxicillin, carbenicillin, oxacillin (OXA), meropenem, imipenem, cefotaxime, cefaclor, kanamycin, ciprofloxacin and tetracycline from Wako Pure Chemical Industries (Osaka, Japan). Chloramphenicol and cefoxitin were purchased from Sigma-Aldrich (St Louis, MO, USA).…”

Section: Test Compoundsmentioning

confidence: 99%

“…To investigate the mechanism of this SYN effect, the non-antibiotic TPPC-derivative BM-TPPC 11 (Figure 1) was used. TPPC is reported to inhibit peptidoglycan biosynthesis by binding to the important lipid carrier prenyl pyrophosphate, and the free carboxylic acids of TPPC are essential for its complexation with prenyl pyrophosphate.…”

Section: Antimicrobial Potentiation With the Combination Of Bm-tppc Amentioning

confidence: 99%

“…TPPC is reported to inhibit peptidoglycan biosynthesis by binding to the important lipid carrier prenyl pyrophosphate, and the free carboxylic acids of TPPC are essential for its complexation with prenyl pyrophosphate. 8,11 In contrast, BM-TPPC does not bind to the target molecule, resulting in the loss of antimicrobial activity. 11 Surprisingly, BM-TPPC still potentiated the anti-MRSA activity of the beta-lactams, as shown in alone showed no antimicrobial activity against MRSA strain IMC B-1109.…”

Section: Antimicrobial Potentiation With the Combination Of Bm-tppc Amentioning

confidence: 99%

“…8,11 In contrast, BM-TPPC does not bind to the target molecule, resulting in the loss of antimicrobial activity. 11 Surprisingly, BM-TPPC still potentiated the anti-MRSA activity of the beta-lactams, as shown in alone showed no antimicrobial activity against MRSA strain IMC B-1109. However, in combination, these two compounds showed lethal SYN activity against MRSA.…”

Section: Antimicrobial Potentiation With the Combination Of Bm-tppc Amentioning

confidence: 99%

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

et al. 2015

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Tripropeptin C (TPPC) is a natural calcium-ion-dependent lipopeptide antibiotic that inhibits peptidoglycan biosynthesis by binding to prenyl pyrophosphate. It displays very potent antimicrobial activity both in vitro and in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) septicemia. The combination of TPPC with all classes of beta-lactams tested (including penam, carbapenem, cephem and oxacephem) showed highly synergistic (SYN) effects against MRSA strains, but not against methicillin-sensitive S. aureus strains. These SYN effects were observed with both a checkerboard methodology and a time-kill analysis. The TPPC analog, bis-methyl ester-TPPC, which has neither antimicrobial activity nor the ability to bind prenyl pyrophosphate, also potentiated the activity of beta-lactams. This result indicates that the mechanism of the SYN activity of TPPC is independent of its binding to prenyl pyrophosphate. Therefore, synergistically enhancing the anti-MRSA activities of TPPC and beta-lactams by combining them is a novel and potentially powerful therapeutic strategy for MRSA infections.

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Advances in Polysaccharide-Based Antimicrobial Delivery Vehicles

Pawar

Bavya

Rohan³

et al. 2020

Racing for the Surface

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Synthesis and antibacterial activity of tripropeptin C derivatives modified at the carboxyl groups

Cited by 10 publications

References 13 publications

Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products

Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products

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

Advances in Polysaccharide-Based Antimicrobial Delivery Vehicles

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