What was old is new again: Phenotypic screening of a unique fungal library yields pyridoxatin, a promising lead against extensively resistant Acinetobacter baumannii (AB5075)

Due to the emergence of resistance, the World Health Organization considers Gram-negative pathogen Acine-tobacter baumannii a top priority for therapeutic development. Using this priority pathogen and a phenotypic, agar plate-based assay, a unique library of extracts from 2500 diverse fungi was screened for antimicrobial activity against a highly virulent, drug-resistant strain of A. baumannii (AB5075). The most potent hit from this screen was an extract from the fungus Tolypocladium sp., which was found to produce pyridoxatin. Another active extract from the fungus Trichoderma deliquescens was characterized and yielded trichokonin VII and trichokonin VIII. Evaluation of pyridoxatin against A. baumannii (AB5075) in a broth microdilution assay revealed a mini-mum inhibitory concentration (MIC) of 38 mu M, compared to the known antibiotic levofloxacin with MIC of 28 mu M. Mass spectrometry, Marfey's analysis and nuclear magnetic resonance spectroscopy analyses confirmed the structures of trichokonins VII and VIII to be consistent with previous reports. In an in vivo Galleria mellonella model, pyridoxatin tested at 150 mg/kg exhibited minimal toxicity (90% survival) and promising antimicrobial efficacy (50% survival) after 5 days. Trichokonins VII and VIII tested at 150 mg/kg were toxic to G. mellonella , with 20% survival and 40% survival after 5 days, respectively. The findings of this project suggest that pyr-idoxatin may serve as a lead compound for the development of antimicrobials against A. baumannii. They also demonstrate the value of the phenotypic screening approach employed herein.

Automated summary

Due to resistance, Acinetobacter baumannii is a top priority for drug development according to the World Health Organization. A library of extracts from 2500 fungi was screened for antimicrobial activity against a drug-resistant strain of A. baumannii, and an extract from the fungus Tolypocladium sp. was found to be the most potent. The extract produced pyridoxatin, which may serve as a lead compound for the development of antimicrobials against A. baumannii.