Adaptation of Mycobacterium tuberculosis to a New Aroylhydrazone Derivative In Vitro and Possible Role of Rv3755c...

We evaluated the response of Mycobacterium tuberculosis to exposure to a new aroylhydrazone derivative using the in vitro mutagenesis followed by genomic analysis of a resistant variant. The compound N'-[(E)-(5-methoxy-1H-indol-3-yl)methylidene]furan-2-carbohydrazide showed minimal inhibitory concentration (MIC) of 0.4412 μM for the reference strain M. tuberculosis H37Rv. An H37Rv clone resistant to elevated (4 × MIC) concentration of this compound recovered on a solid medium was further analyzed by whole genome sequencing and bioinformatics tools. A non-synonymous mutation was detected in the Rv3755c gene at position 302A>G (codon 101H>R, CAC-CGC). The gene-gene interaction analysis showed that this gene belongs to a network that also includes several ABC transporter genes. The identified mutation in Rv3755c may be associated with bacterial adaptation to the selective pressure of the studied aroylhydrazone derivative and reflect a non-specific drug tolerance mechanism. The conserved M. tuberculosis protein Rv3755c, whose function is unknown, may be related to the ABC transporter efflux system.