Thiopeptides: antibiotics with unique chemical structures and diverse biological activities

Chan, Derek C. K.; Burrows, Lori L.

doi:10.1038/s41429-020-00387-x

Cited by 51 publications

(45 citation statements)

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“…Thiopeptides represent a very promising class of neglected antimicrobials. Despite their potent antimicrobial activity thiopeptides have been poorly exploited in therapeutic treatments so far due to the high rate of resistance development, challenging synthesis, poor aqueous solubility and associated low bioavailability (53). In this work we describe a cost-efficient production of the thiopeptide MP1 and show that MP1 in combination with rifampicin had very good synergistic effects on MRSA.…”

Section: Discussionmentioning

confidence: 94%

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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Section: Discussionmentioning

confidence: 94%

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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“…Thiazolines and thiazole are replete in natural products [42][43][44] and synthetic drug-like small molecules, 8,9 and calculations confirm the expected decrease in conformational freedom that derives from aromatic and/or sp 2 character within the peptide backbone. 45 This finding and the leader-independent nature of MicD-F and ArtGox-mediated thiazol(in)e biosynthesis inspired us to explore substrates in which the site of cyclodehydration/dehydrogenation is embedded within a stable protein fold (Figure 4).…”

Section: Redirecting Ripp Biosynthetic Enzymes To Intact Folded Proteinsmentioning

confidence: 85%

Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates

Walker¹,

Hamlish²,

Tytla³

et al. 2022

Preprint

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products that include the FDA-approved analgesic ziconotide1,2 as well as compounds with potent antibiotic, antiviral, and anticancer properties.3 RiPP enzymes known as cyclodehydratases and dehydrogenases represent an exceptionally well-studied enzyme class.3 These enzymes work together to catalyze intramolecular, interresidue condensation3,4 and aromatization reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers, including aramids and beta-amino acids, within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse, non-alpha-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond. Both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. Moreover, as thiazoles and thiazoline heterocycles are replete in natural products,5,6,7 small molecule drugs,8,9 and peptide-mimetic therapeutics,10 their installation in protein-based biotherapeutics could improve or augment performance, activity, stability, and/or selectivity. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code.

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“…Likewise, the BCG for micrococcin P1 resided on a 23 kb contig in S. felis C4 with several plasmid associated genes present. Micrococcin P1 is known to be active predominantly against gram-positive bacteria, targeting the L11 binding domain of the 23 S ribosomal RNA, thereby inhibiting translation ( Chan and Burrows, 2020 ). A similar mode of action was observed from the cytological and ultrastructural profiles of bacteria exposed to S. felis C4 extract, resulting in condensed nuclei and toroid shaped chromosomes, indicative of stalled translation.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius

O’Neill

Worthing

Kulkarni

et al. 2021

eLife

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Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is an important emerging zoonotic pathogen that causes severe skin infections. To combat infections from drug-resistant bacteria, the transplantation of commensal antimicrobial bacteria as a therapeutic has shown clinical promise. We screened a collection of diverse staphylococcus species from domestic dogs and cats for antimicrobial activity against MRSP. A unique strain (S. felis C4) was isolated from feline skin that inhibited MRSP and multiple gram-positive pathogens. Whole genome sequencing and mass spectrometry revealed several secreted antimicrobials including a thiopeptide bacteriocin micrococcin P1 and phenol-soluble modulin beta (PSMβ) peptides that exhibited antimicrobial and anti-inflammatory activity. Fluorescence and electron microscopy revealed that S. felis antimicrobials inhibited translation and disrupted bacterial but not eukaryotic cell membranes. Competition experiments in mice showed that S. felis significantly reduced MRSP skin colonization and an antimicrobial extract from S. felis significantly reduced necrotic skin injury from MRSP infection. These findings indicate a feline commensal bacterium that could be utilized in bacteriotherapy against difficult-to-treat animal and human skin infections.

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Thiopeptides: antibiotics with unique chemical structures and diverse biological activities

Cited by 51 publications

References 100 publications

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

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

Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius

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