Total synthesis of micrococcin P1 and thiocillin I enabled by Mo(<scp>vi</scp>) catalyst

Akasapu, Siddhartha; Hinds, Aaron B; Powell, Wyatt; Walczak, M

doi:10.1039/c8sc04885a

Cited by 28 publications

(28 citation statements)

References 47 publications

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“…Thus, 1 was presumed to occur in its natural configuration as shown in Figure 1 . This assumption was supported by comparison of the optical rotation and NMR data of 1 with those of 2 , the configuration of which was confirmed by total synthesis [ 6 , 10 ].…”

Section: Resultsmentioning

confidence: 84%

A New Thiopeptide Antibiotic, Micrococcin P3, from a Marine-Derived Strain of the Bacterium Bacillus stratosphericus

et al. 2020

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A new thiopeptide (micrococcin P3, 1) and a known one (micrococcin P1, 2) were isolated from the culture broth of a marine-derived strain of Bacillus stratosphericus. The structures of both compounds were elucidated using spectroscopic methods, including extensive 1D and 2D NMR analysis, high resolution mass spectrometry (HRMS), and tandem mass spectrometry. Both compounds exhibited potent antibacterial activities against Gram-positive strains with minimum inhibitory concentration (MIC) values of 0.05−0.8 μg/mL and did not show cytotoxicity in the MTT assay up to a concentration of 10 μM. This study adds a new promising member, micrococcin P3, to the family of thiopeptide antibiotics, which shows potential for the development of new antibiotics targeting Gram-positive bacteria.

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Section: Resultsmentioning

confidence: 84%

A New Thiopeptide Antibiotic, Micrococcin P3, from a Marine-Derived Strain of the Bacterium Bacillus stratosphericus

et al. 2020

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“…The in vitro ability of garvicin KS to eradicate S. aureus biofilms is strain-dependent and is not augmented by micrococcin P1 Previous reports indicated that garvicin KS is effective in inhibiting the growth of S. aureus in liquid culture 42 , whereas micrococcin P1 has recently been regarded as a promising therapeutic alternative to antibiotics against MRSA and mycobacterial infections 43,44 . The antimicrobial potential of these bacteriocins, however, has never been assessed on clinically relevant S. aureus strains and, moreover, in a biofilm setting.…”

Section: Resultsmentioning

confidence: 99%

A bacteriocin-based antimicrobial formulation to effectively disrupt the cell viability of methicillin-resistant Staphylococcus aureus (MRSA) biofilms

Kranjec

Ovchinnikov

Grønseth

et al. 2020

npj Biofilms Microbiomes

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Antibiotic-resistant and biofilm-associated infections brought about by methicillin-resistant Staphylococcus aureus (MRSA) strains is a pressing issue both inside as well as outside nosocomial environments worldwide. Here, we show that a combination of two bacteriocins with distinct structural and functional characteristics, garvicin KS, and micrococcin P1, showed a synergetic antibacterial activity against biofilms produced in vitro by S. aureus, including several MRSA strains. In addition, this bacteriocin-based antimicrobial combination showed the ability to restore the sensitivity of the highly resilient MRSA strain ATCC 33591 to the β-lactam antibiotic penicillin G. By using a combination of bacterial cell metabolic assays, confocal and scanning electron microscopy, we show that the combination between garvicin KS, micrococcin P1, and penicillin G potently inhibit cell viability within S. aureus biofilms by causing severe cell damage. Together these data indicate that bacteriocins can be valuable therapeutic tools in the fight against biofilm-associated MRSA infections.

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“…Several attempts have been made to synthesize MP1 chemically to reduce its cost and possibly modify its structure to make it more water-soluble, but so far these synthetic approaches are not scalable and cost-effective (54,55). To improve the effectiveness of MP1 production, fermentation can be an alternative to synthetic approaches.…”

Section: Discussionmentioning

confidence: 99%

A Strong Synergy Between the Thiopeptide Bacteriocin Micrococcin P1 and Rifampicin Against MRSA in a Murine Skin Infection Model

et al. 2021

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Antibiotic-resistant bacterial pathogens have become a serious threat worldwide. One of these pathogens is methicillin-resistant Staphylococcus aureus (MRSA), a major cause of skin and soft tissue infections. In this study we identified a strain of Staphylococcus equorum producing a substance with high antimicrobial activity against many Gram-positive bacteria, including MRSA. By mass spectrometry and whole genome sequencing the antimicrobial substance was identified as the thiopeptide bacteriocin micrococcin P1 (MP1). Based on its properties we developed a one-step purification protocol resulting in high yield (15 mg/L) and high purity (98%) of MP1. For shorter incubation times (5-7 h) MP1 was very potent against MRSA but the inhibitory effect was overshadowed by resistance development during longer incubation time (24h or more). To overcome this problem a synergy study was performed with a number of commercially available antibiotics. Among the antibiotics tested, the combination of MP1 and rifampicin gave the best synergistic effect, with MIC values 25 and 60 times lower than for the individual drugs, respectively. To assess the therapeutic potential of the MP1-rifampicin combination, we used a murine skin infection model based on the use of the multidrug-resistant luciferase-tagged MRSA strain Xen31. As expected, neither of the single antimicrobials (MP1 or rifampicin) could eradicate Xen31 from the wounds. By contrary, the MP1-rifampicin combination was efficient not only to eradicate but also to prevent the recurrence of Xen31 infection. Furthermore, compared to fucidin cream, which is commonly used in skin infection treatments, MP1-rifampicin combination was superior in terms of preventing resistance development. Our results show that combining MP1, and probably other thiopeptides, with antibiotics can be a promising strategy to treat SSTIs caused by MRSA and likely many other Gram-positive bacteria.

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Total synthesis of micrococcin P1 and thiocillin I enabled by Mo(vi) catalyst

Abstract: Total synthesis of two thiopeptide antibiotics, micrococcin P1 and thiocillin I, is described featuring new molybdenum catalyst.

Cited by 28 publications

References 47 publications

A New Thiopeptide Antibiotic, Micrococcin P3, from a Marine-Derived Strain of the Bacterium Bacillus stratosphericus

A New Thiopeptide Antibiotic, Micrococcin P3, from a Marine-Derived Strain of the Bacterium Bacillus stratosphericus

A bacteriocin-based antimicrobial formulation to effectively disrupt the cell viability of methicillin-resistant Staphylococcus aureus (MRSA) biofilms

A Strong Synergy Between the Thiopeptide Bacteriocin Micrococcin P1 and Rifampicin Against MRSA in a Murine Skin Infection Model

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