Gao, C.-H. | bioRxiv Science

bioRxiv2025

A biofilm activator MmtA1 modulates multi-drug resistance in mycobacteria

When exposed to the antibiotic-induced stress, Mycobacterium species have the ability to survive by forming protective multicellular structures known as biofilms. However, the underlying mechanism of biofilm formation in response to antibiotics is not fully understood. In this study, we identified a transcriptional factor, MmtA1, which responds to the first-line anti-tuberculosis drug isoniazid and regulates genes involved in sugar and lipid transportation. This leads to increased biofilm formation and multi-drug resistance in M. smegmatis. These findings suggest that isoniazid may act as a molecular messenger, working in coordination with transcriptional regulatory factors to induce multidrug resistance under chemotherapy. ImportanceThis study elucidates a novel transcriptional regulatory mechanism by which Mycobacterium smegmatis develops multidrug resistance in response to the anti-tuberculosis drug isoniazid. By linking antibiotic stress to transcriptional regulation and metabolic adaptation, this work provides new insights into drug-induced tolerance in mycobacteria, suggesting antibiotic functional as inducer of biofilm formation, triggering a coordinated transcriptional response to enhance bacterial survival under antibiotic pressure.

microbiology↗

bioRxiv2018

Co-culture of soil biofilm isolates enables the discovery of novel antibiotics

Bacterial natural products (NPs) are considered to be a promising source of drug discovery. However, the biosynthesis gene clusters (BGCs) of NP are not often expressed, making it difficult to identify them. Recently, the study of biofilm community showed bacteria may gain competitive advantages by the secretion of antibiotics, implying a possible way to screen antibiotic by evaluating the social behavior of bacteria. In this study, we have described an efficient workflow for novel antibiotic discovery by employing the bacterial social interaction strategy with biofilm cultivation, co-culture, transcriptomic and genomic methods. We showed that a biofilm dominant species, i.e. Pseudomonas sp. G7, which was isolated from cultivated soil biofilm community, was highly competitive in four-species biofilm communities, as the synergistic combinations preferred to exclude this strain while the antagonistic combinations did not. Through the analysis of transcriptomic changes in four-species co-culture and the complete genome of Pseudomonas sp. G7, we finally discovered two novel non-ribosomal polypeptide synthetic (NRPS) BGCs, whose products were predicted to have seven and six amino acid components, respectively. Furthermore, we provide evidence showing that only when Pseudomonas sp. G7 was co-cultivated with at least two or three other bacterial species can these BGC genes be induced, suggesting that the co-culture of the soil biofilm isolates is critical to the discovery of novel antibiotics. As a conclusion, we set a model of applying microbial interaction to the discovery of new antibiotics.

microbiology↗