Berton, S. | bioRxiv Science

bioRxiv2022

Discovery of benzophenanthridine derivatives with potent activity against multidrug resistant Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug-resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPD). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 [~] 2-10 M) against multiple Mycobacterium strains, while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb viability within infected macrophages. The two BPD compounds displayed comparable efficacy to rifampicin, a critical frontline antibiotic used for the prevention and treatment of TB. Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates, suggesting a completely novel mechanism of action compared to existing frontline TB dugs. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery. TOC/GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/515485v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1536acaorg.highwire.dtl.DTLVardef@1881e83org.highwire.dtl.DTLVardef@18b2f58org.highwire.dtl.DTLVardef@d15f1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Transcriptome and chromatin accessibility mapping reveals a type I interferon response triggered by Mycobacterium tuberculosis infection

Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. The success of Mtb as a human pathogen depends on its ability to manipulate host immune response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, may play a role in the regulation of chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout ({Delta}PPM1A) and PPM1A overexpressing (PPM1A+) macrophages, we demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression signatures. The strongest concordant chromatin accessibility and gene expression signature triggered by Mtb infection was enriched for genes involved in the type I interferon (IFN) signaling pathways. Modulation of PPM1A expression results in altered chromatin accessibility signatures during Mtb infection that are reflected in the total number, chromosome location and directionality of change. Transcription factor motif analysis revealed an enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including IRF4, MEF2A, and JDP2. In contrast, both deletion and overexpression of PPM1A produced unique transcription factor enrichment signatures linked to the genomic regions with altered chromatin accessibility. Our study demonstrates that altered type I IFN responses in Mtb-infected macrophages occurs as a result of genome-wide changes in chromatin accessibility, and that PPM1A likely plays a role in a subset of these signatures.

genomics↗