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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 novelbenzo[c]phenanthridinederivatives (BPD). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90∼ 2-10 μM) against multipleMycobacteriumstrains, 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

The prevalence of lung disease caused by Mycobacterium abscessus is increasing among patients with cystic fibrosis. M. abscessus is a multidrug resistant opportunistic pathogen that is notoriously difficult to treat due to a lack of efficacious therapeutic regimens. Currently, there are no standard regimens, and treatment guidelines are based empirically on drug susceptibility testing. Thus, novel antibiotics are required. Natural products represent a vast pool of biologically active compounds that have a history of being a good source of antibiotics. Here, we screened a library of 517 natural products purified from fermentations of various bacteria and fungi against M. abscessus ATCC 19977. Lysobactin and sorangicin A were active against the M. abscessus complex and drug resistant clinical isolates. These natural products merit further consideration to be included in the M. abscessus drug pipeline.

The production of itaconate by macrophages was only discovered in 2011. A rapidly increasing number of studies have since revealed essential biological roles for itaconate, ranging from antimicrobial to immunomodulator. Itaconate has been estimated to reach low-millimolar concentrations in activated macrophages, including those within infected lungs and brains, whereas itaconate’s MIC towards several bacterial strains were measured to be in the low-to-mid-millimolar range, casting some doubts on the antibacterial role of itaconate in vivo. Several of these investigations, in particular those measuring MIC values of itaconate or itaconic acid, have however tended to ignore the high acidity of this small diacid (pKas 3.85 and 5.45), thereby potentially biasing the MIC measurements. We report herein that: 1) at high concentration, itaconic acid can significantly reduce the pH of growth media; 2) the antibacterial activity of itaconate increases in a synergistic manner with acidity; 3) this synergistic effect is not simply due to increased permeability of monoanionic itaconate; 4) considering that the MIC of itaconate is many fold lower under acidic conditions for all strains tested, itaconate may serve an antimicrobial role, particularly in acidic vesicles such as the phagolysosome; and 5) differential growth behavior in the presence of disodium itaconate versus itaconic acid may serve to rapidly screen bacterial strains for their ability to metabolize itaconate. Our results further support the hypothesis that inhibitors of itaconate degradation in bacteria may provide a new strategy to treat infections.