Lung infections caused by Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and to other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug-resistant pathogen showing resistance to even standard antituberculosis drugs, such as rifampin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2,700 approved drugs was screened at a single-point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose-response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampin derivative rifabutin had MICs of 3 ± 2 μM (3 μg/ml) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T, and M. abscessus subsp. massiliense CCUG 48898-T, as well as against a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin-resistant strains. In conclusion, rifabutin, in contrast to rifampin, is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

Lung disease caused by Mycobacterium abscessus is increasing, and current clarithromycin-based treatment regimens are only moderately effective. Here, we determined the effect of clarithromycin-vancomycin combination against M. abscessus complex isolates in vitro. Synergy was found with a fractional inhibitory concentration index (FICI) score of ≤0.5 and a 4- to 10-fold decrease in MIC.

BackgroundMycobacteria, along with exospore forming Streptomyces, belong to the phylum actinobacteria. Mycobacteria are generally believed to be non-differentiating. Recently however, we showed that the mycobacterial model organism M. smegmatis is capable of forming different types of morphologically distinct resting cells. When subjected to starvation conditions, cells of M. smegmatis exit from the canonical cell division cycle, segregate and compact their chromosomes, and become septated and multi-nucleoided. Under zero nutrient conditions the differentiation process terminates at this stage with the formation of Large Resting Cells (LARCs). In the presence of traces of carbon sources this multi-nucleoided cell stage completes cell division and separates into Small Resting Cells (SMRCs). Here, we carried out RNA-seq profiling of SMRC and LARC development to characterize the transcriptional program underlying these starvation-induced differentiation processes.ResultsChanges among the top modulated genes demonstrated that SMRCs and LARCs undergo similar transcriptional changes. The formation of multi-nucleoided cells (i.e. LARCs and the LARC-like intermediates observed during SMRC formation) was accompanied by upregulation of septum formation functions FtsZ, FtsW, and PbpB, as well as the DNA translocase FtsK. The observed compaction of chromosomes was accompanied by an increase of the transcript level of the DNA binding protein Hlp, an orthologue of the Streptomyces spore-specific chromosome condensation protein HupS. Both SMRC and LARC development were accompanied by similar temporal expression patterns of candidate regulators, including the transcription factors WhiB2, WhiB3, and WhiB4, which are orthologues of the Streptomyces sporulation regulators WhiB, WhiD and WblA, respectively.ConclusionsTranscriptional analyses of the development of mycobacterial resting cell types suggest that these bacteria harbor a novel differentiation program and identify a series of potential regulators. This provides the basis for the genetic dissection of this actinobacterial differentiation process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3190-4) contains supplementary material, which is available to authorized users.

We determined the microbicidal activities of antibacterials against nonreplicating Mycobacterium smegmatis grown in a starvation-based Loebel model for persistence. Whereas most drugs lost their activity, fluoroquinolones retained lethal potency. Dose-response characterizations showed a paradoxical more-drug-kills-less Eagle effect. Pretreatment of cultures with chloramphenicol blocked the lethal action of the gyrase inhibitors. These results suggest that fluoroquinolones at low concentrations trigger a protein synthesis-dependent cell death pathway and shut off this suicide pathway at elevated concentrations.