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Cycloaddition reactions such as intramolecular Diels–Alder (IMDA) are extremely important in constructing multicyclic scaffolds with diverse bioactivities. Using MycB as a biomarker, three new polyketides – Chaetolivacines A (1), B (3), and C (4) – with one known compound Myceliothermophin E (2) comprising of decalin and 4-hydroxy-2-pyridones were obtained from the culture of Chaetomium olivaceum SD-80A under the guidance of gene mining. The structures of these compounds were established using detailed 1D, 2D NMR, and high-resolution electron spray ionization mass spectroscopy (HRESIMS) analysis. The relative and absolute configurations of the compounds 1, 3, and 4 were elucidated by NOESY and ECD. The biosynthesis pathways of these compounds were proposed, which involves in three key genes ChaA [polyketide synthase-non-ribosomal peptide synthetases (PKS-NRPS)], ChaB, and ChaC. Compounds 1–4 were tested for their antimicrobial activities, and compounds 2 and 3 showed moderate bioactivity against Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) with MIC values of 15.8 and 27.1 μM. The results showed that configuration of C-21 in 3 and 4 is important for anti-SA and anti-MRSA activities. This study reveals the significant potential of the genus Chaetomium in producing new PKS-NRPS, therefore increasing the speed in the mining for new sources of antimicrobial agents.

Cycloaddition reactions such as intramolecular Diels–Alder (IMDA) are extremely important in constructing multicyclic scaffolds with diverse bioactivities. Using MycB as a biomarker, three new polyketides – Chaetolivacines A (1), B (3), and C (4) – with one known compound Myceliothermophin E (2) comprising of decalin and 4-hydroxy-2-pyridones were obtained from the culture of Chaetomium olivaceum SD-80A under the guidance of gene mining. The structures of these compounds were established using detailed 1D, 2D NMR, and high-resolution electron spray ionization mass spectroscopy (HRESIMS) analysis. The relative and absolute configurations of the compounds 1 , 3 , and 4 were elucidated by NOESY and ECD. The biosynthesis pathways of these compounds were proposed, which involves in three key genes ChaA [polyketide synthase-non-ribosomal peptide synthetases (PKS-NRPS)], ChaB , and ChaC. Compounds 1 – 4 were tested for their antimicrobial activities, and compounds 2 and 3 showed moderate bioactivity against Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) with MIC values of 15.8 and 27.1 μM. The results showed that configuration of C-21 in 3 and 4 is important for anti-SA and anti-MRSA activities. This study reveals the significant potential of the genus Chaetomium in producing new PKS-NRPS, therefore increasing the speed in the mining for new sources of antimicrobial agents. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) pose a significant health threat as they tend to cause severe infections in vulnerable populations and are difficult to treat due to a limited range of effective antibiotics and also their ability to form biofilm. These organisms were once limited to hospital acquired infections but are now widely present in the community and even in animals. Furthermore, these organisms are constantly evolving to develop resistance to more antibiotics. This results in a need for new clinically useful antibiotics and one potential source are the Streptomyces which have already been the source of several anti-MRSA drugs including vancomycin. There remain large numbers of Streptomyces potentially undiscovered in underexplored regions such as mangrove, deserts, marine, and freshwater environments as well as endophytes. Organisms from these regions also face significant challenges to survival which often result in the production of novel bioactive compounds, several of which have already shown promise in drug development. We review the various mechanisms of antibiotic resistance in MRSA and all the known compounds isolated from Streptomyces with anti-MRSA activity with a focus on those from underexplored regions. The isolation of the full array of compounds Streptomyces are potentially capable of producing in the laboratory has proven a challenge, we also review techniques that have been used to overcome this obstacle including genetic cluster analysis. Additionally, we review the in vivo work done thus far with promising compounds of Streptomyces origin as well as the animal models that could be used for this work.

Methicillin-resistant Staphylococcus aureus (MRSA) pose a significant health threat as they tend to cause severe infections in vulnerable populations and are difficult to treat due to a limited range of effective antibiotics and also their ability to form biofilm. These organisms were once limited to hospital acquired infections but are now widely present in the community and even in animals. Furthermore, these organisms are constantly evolving to develop resistance to more antibiotics. This results in a need for new clinically useful antibiotics and one potential source are the Streptomyces which have already been the source of several anti-MRSA drugs including vancomycin. There remain large numbers of Streptomyces potentially undiscovered in underexplored regions such as mangrove, deserts, marine, and freshwater environments as well as endophytes. Organisms from these regions also face significant challenges to survival which often result in the production of novel bioactive compounds, several of which have already shown promise in drug development. We review the various mechanisms of antibiotic resistance in MRSA and all the known compounds isolated from Streptomyces with anti-MRSA activity with a focus on those from underexplored regions. The isolation of the full array of compounds Streptomyces are potentially capable of producing in the laboratory has proven a challenge, we also review techniques that have been used to overcome this obstacle including genetic cluster analysis. Additionally, we review the in vivo work done thus far with promising compounds of Streptomyces origin as well as the animal models that could be used for this work. [ABSTRACT FROM AUTHOR]