Bioinformatic Approaches Identify Hybrid Antibiotics against Tuberculosis via d-Amino Acid-Activating Adenylation Domains from Cordyceps militaris .

The development of tuberculosis (TB) therapy has been marked by the discovery of natural-product-derived streptomycin, followed by the introduction of NP-derived rifampicin, representing a significant milestone in the history of TB management. However, TB remains a global challenge, with the emergence of multidrug-resistant Mycobacterium tuberculosis highlighting the need for novel therapeutic agents. In this study, a bioinformatic approach was employed to investigate d-amino acid-activating adenylation domains, leading to the identification of cordysetin A ( 1 ), a novel trans -decalin tetramic acid antibiotic from the ascomycete fungi Cordyceps militaris . Cordysetin A ( 1 ) exhibits considerable activity against M. tuberculosis in vitro and in vivo while maintaining low cytotoxicity. These results reveal that the d-configuration of the amino acid within this hybrid polyketide-nonribosomal antibiotic is crucial for preserving its anti-tuberculosis efficacy. These findings emphasize the significant translational potential of cordysetin A as a promising candidate for TB treatment, furthering our understanding of bioinformatic approaches in the development of effective anti-tuberculosis agents.