Chrysomycin A inhibits the topoisomerase I of Mycobacterium tuberculosis

Muralikrishnan, Balaji; Edison, Lekshmi K.; Dusthackeer, Azger; Jijimole, G R; Ramachandran, Ranjit; Madhavan, Aravind; Kumar, Ram Mohan Ram

doi:10.1038/s41429-022-00503-z

Cited by 11 publications

(9 citation statements)

References 26 publications

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“…OA161 possesses potent antimycobacterial activity and effectively killed drug-resistant strains of M. tuberculosis (21,22). In the present study, we report a novel role for MmpL5 and MmpS5 complex in conferring resistance to chrysomycin A.…”

Section: Introductionmentioning

confidence: 52%

“…Isolation and whole-genome sequence analysis of chrysomycin resistant mutants of M. smegmatis Chrysomycin A displays potent antimycobacterial activity, and our recent study has shown its bactericidal activity emanates from inhibition of topoisomerase I and DNA gyrase (22). It therefore, became necessary to further understand the mechanisms of resistance to this antibiotic.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, chrysomycin A has been reported to have potent bactericidal activity against drug-resistant clinical strains of M. tuberculosis and other Mycobacterium species (21,22).…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in <i>Mycobacterium smegmatis</i>

Salini¹,

Muralikrishnan²,

Bhat³

et al. 2022

Preprint

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Mycobacterium tuberculosis is a leading cause of human mortality worldwide and the emergence of drug-resistantstrains, demands the discovery of new classes of antimycobacterials that can be employed in the therapeutic pipeline. Previously, a secondary metabolite Chrysomycin A, isolated from Streptomyces sp. OA161 was shown to have potent bactericidal activity against drug-resistant clinical isolates of M. tuberculosis and different species of mycobacteria. The antibiotic inhibits the mycobacterial topoisomerase I and DNA gyrase leading to bacterial death, but the mechanisms that could cause resistance are currently unknown. To further understand the resistance mechanism, spontaneous resistance mutants were isolated and subjected to whole-genome sequencing. Mutation in a TetR family transcriptional regulator MSMEG_1380 was identified in the resistant isolates and was close to an operon encoding membrane protein MSMEG_1381 and MSMEG_1382. Sequence analysis and modeling studies indicated that they are components of the Mmp family of efflux pumps and over-expression of either the operon or individual genes conferred resistance to chrysomycin A, isoniazid, and ethambutol that are in TB therapy. Our study highlights the role of membrane transporter proteins in conferring multiple drug resistance and the utility of recombinant strains overexpressing membrane transporters in the drug screening pipeline.

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Section: Introductionmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

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Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in <i>Mycobacterium smegmatis</i>

Salini¹,

Muralikrishnan²,

Bhat³

et al. 2022

Preprint

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“…However, compared with polymyxin B, CA has poor inhibitory activity against Gram-negative bacteria Pseudomonas aeruginosa PAO1, with the MIC values of 4 μg/mL and 64 μg/mL, respectively. The previous literature had only explored the activity of CA against Gram-positive bacteria, such as Bacillus subtilis and Mycobacterium tuberculosis [ 35 , 36 ]. The different activities and mechanisms of CA against Gram-negative and Gram-positive bacteria deserve further exploration.…”

Section: Resultsmentioning

confidence: 99%

Formulation of Chrysomycin A Cream for the Treatment of Skin Infections

et al. 2022

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Chrysomycin A, a compound derived from marine microorganisms, proved to have a specific great in vitro inhibitory effect on methicillin-resistant Staphylococcus aureus (MRSA). It exhibits high safety for the skin, as well as a better therapeutic effect than the current clinical drug, vancomycin. Nevertheless, its poor water solubility highly limits the application and reduces the bioavailability. In view of this, we developed a cream of chrysomycin A (CA) to enhance the solubility for the treatment of skin infection, while avoiding the possible toxicity caused by systemic administration. A comprehensive orthogonal evaluation system composed of appearance, spreading ability, and stability was established to find the optimal formula under experimental conditions. The final product was odorless and easy to be spread, with a lustrous, smooth surface. The particle size of the product met Chinese Pharmacopoeia specifications and the entire cream showed long-term stability in destructive tests. The in vitro and in vivo studies indicated that CA cream had a similar anti-MRSA activity to commercially available mupirocin, showing its potential as an efficacious topical delivery system for skin infections treatment.

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“…Chrysomycin analogs are one group of glycosides with a benzonaphthopyranone structure obtained from several Streptomyces strains [ 8 , 9 ], which display a broad spectrum of biological properties, including anti-phage, anti-bacterial, and cytotoxic activities [ 10 , 11 , 12 , 13 ]. Especially, chrysomycin A ( Figure 1 ) showed a potent inhibitory effect on multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis , methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) [ 13 , 14 , 15 , 16 ]. Chrysomycin A was originally isolated from strain Streptomyces A-419 in 1955 as a mixture with chrysomycin B [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Genomic Analysis of Marine Strain Streptomyces sp. 891, an Excellent Producer of Chrysomycin A with Therapeutic Potential

Tang

Liu

et al. 2022

Marine Drugs

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Chrysomycin A is one of the most promising therapeutic candidates for treating infections caused by multidrug-resistant Gram-positive bacteria. By hybridizing next-step generation (Illumina) and third-generation (PacBio) sequencing technologies, a high-quality chromosome-level genome together with a plasmid was firstly assembled for chrysomycin A-producing marine strain 891. Phylogenetic analysis of the 16S rRNA gene and genome sequences revealed that this strain unambiguously belonged to the genus Streptomyces, and its genomic features and functional genes were comprehensively analyzed and annotated. AntiSMASH analysis of this strain unveiled one key biosynthetic gene cluster, T2PKS, responsible for the biosynthesis of chrysomycin, the biosynthesis pathway of which was putatively proposed. These findings definitely shed light on further investigation for construction of a robust industrial strain with high-yield chrysomycin A production using genetic engineering techniques and combinatorial biology approaches.

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Chrysomycin A inhibits the topoisomerase I of Mycobacterium tuberculosis

Cited by 11 publications

References 26 publications

Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in <i>Mycobacterium smegmatis</i>

Overexpression of a Membrane Transport System MSMEG_1381 and MSMEG_1382 Confers Multidrug Resistance in <i>Mycobacterium smegmatis</i>

Formulation of Chrysomycin A Cream for the Treatment of Skin Infections

Comprehensive Genomic Analysis of Marine Strain Streptomyces sp. 891, an Excellent Producer of Chrysomycin A with Therapeutic Potential

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