Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and ...immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo1,5-apyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log
CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.
Pulmonary nontuberculous mycobacteria (NTM) disease is of increasing public health concern in China. Information is limited regarding risk factors associated with this disease in China. The objective ...of this study was to describe the epidemiology of pulmonary disease due to NTM in Southern China.
We retrospectively reviewed the medical records of pulmonary NTM patients registered in the Guangzhou Chest Hospital with positive mycobacterial cultures during 2013-2016. We described sex, age, residence, treatment history, laboratory examination results and comorbidities of pulmonary NTM patients.
Among the 607 NTM cases, the most prevalent species were Mycobacterium avium complex (44.5%), Mycobacterium abscessus complex (40.5%), Mycobacterium kansasii (10.0%) and Mycobacterium fortuitum (2.8%). The male:female ratio was significantly lower among patients infected with rapidly growing mycobacteria (RGM) than among those with slowly growing mycobacteria (SGM). The risk of developing SGM disease significantly increased with advancing age. In addition, pulmonary RGM diseases were more common in migrant population than resident population. Notably, patients with pulmonary RGM diseases were significantly more likely to have bronchiectasis underlying noted than those with SGM diseases. No significant difference was observed in in vitro drug susceptibility among NTM species.
Our data illustrate that the M. avium complex is the most predominant causative agent of pulmonary NTM disease in Southern China. Female, migrant population, the presence of bronchiectasis are independent risk factors for pulmonary diseases due to RGM. In addition, the prevalence of SGM increases significantly with advancing age.
Pulmonary tuberculosis is a chronic infectious disease of the respiratory system. It is still one of the leading causes of death from a single infectious disease, but it has been stuck in the study ...of a single pathogen. Recent studies have shown that many diseases are associated with disruption of the native microbiota. In this study we investigated the occurrence of tuberculosis and the correlation between drug resistance and respiratory flora. High-throughput 16 S rRNA gene sequencing was used to characterize the respiratory microbiota composition of 30 tuberculosis (TB) affected patients and compared with 30 healthy (H) controls. According to their Gene Xpert results, 30 pulmonary tuberculosis patients were divided into 12 persons in the drug-sensitive group (DS0) and 18 persons in the drug-resistant group (DR0). The microbial flora of the two were compared with the H group.
The data generated by sequencing showed that Firmicutes, Proteus, Bacteroides, Actinomyces and Fusobacterium were the five main bacterial phyla detected, and they constituted more than 96% of the microbial community. The relative abundances of Fusobacterium, Haemophilus, Porphyromonas, Neisseria, TM7, Spirochetes, SR1, and Tenericutes in the TB group was lower than that of the H group, and Granulicatella was higher than the H group. The PcoA diagrams of the two groups had obvious clustering differences. The Alpha diversity of the TB group was lower than that of the H group, and the Beta diversity was higher than that of the H group (P < 0.05). The relative abundance of Streptococcus in the DS0 group was significantly higher than that in the DR0 group (P < 0.05).
Pulmonary tuberculosis can cause disorders of the respiratory tract microbial flora, in which the relative abundance of Streptococcus was significantly different between rifampicin-sensitive and rifampicin-resistant patients.
Pyrazinamide (PZA), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. While the mechanism of activation of this prodrug into pyrazinoic acid (POA) by
has ...been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. Here, we report how a new PZA resistance determinant, the Asp67Asn substitution in Rv2783, confers
resistance to PZA. Expression of the mutant allele but not the wild-type allele in
recapitulates the PZA resistance observed in clinical isolates. In addition to catalyzing the metabolism of RNA and single-stranded DNA, Rv2783 also metabolized ppGpp, an important signal transducer involved in the stringent response in bacteria. All catalytic activities of the wild-type Rv2783 but not the mutant were significantly inhibited by POA. These results, which indicate that Rv2783 is a target of PZA, provide new insight into the molecular mechanism of the sterilizing activity of this drug and a basis for improving the molecular diagnosis of PZA resistance and developing evolved PZA derivatives to enhance its antituberculosis activity.
We have conducted a multicenter study of the diagnostic accuracy of the MTBDRplus 2.0 assay in compared with conventional and molecular reference standard in four tuberculosis (TB)-specialized ...hospitals of China. A total of 5038 patients were enrolled in this study. The overall sensitivity of the assay for the diagnosis of TB was 92.7% 1723/1858, 95% confidence interval (95% CI): 91.5-93.9. In smear-positive/culture-positive cases the sensitivity was 97.7% (995/1018, 95% CI: 96.6-98.6), whereas in smear-negative/culture-positive cases it was 86.7% (728/840, 95% CI: 84.2-88.9). The agreement rate between MTBDRplus 2.0 and Xpert MTB/RIF was 97.7% (1015/1039, 95% CI: 96.6-98.5) for smear-positive cases and 97.0% (3682/3794, 95% CI: 96.5-97.6) for smear-negative cases. As compared with phenotypic drug susceptibility testing, the MTBDRplus 2.0 correctly identified 298 of 315 patients (94.6%, 95% CI: 91.5-96.8) with rifampicin-resistance. As noted previously, isoniazid resistance is associated with many different mutations and consequently the sensitivity compared to phenotypic testing was lower (81.0%, 95% CI: 76.8-84.7). In conclusion, this assay is a rapid, accurate test in terms of increased sensitivity for detecting smear-negative TB patients, as well as an alternative for detecting both RIF and INH resistance in persons with presumptive TB, whereas the absence of a mutation in the specimens must be interpreted cautiously.
is a fast growing
species mainly causing skin and respiratory infections in human.
is resistant to numerous drugs, which is a major challenge for the treatment. In this study, we have sequenced the ...genomes of two clinical
strains having rough and smooth morphology, using the single molecule real-time and Illumina HiSeq sequencing technology. In addition, we reported the first comparative methylome profiles of a rough and a smooth
clinical strains. The number of N4-methylcytosine (4mC) and N6-methyladenine (6mA) modified bases obtained from smooth phenotype were two-fold and 1.6 fold respectively higher than that of rough phenotype. We have also identified 4 distinct novel motifs in two clinical strains and genes encoding antibiotic-modifying/targeting enzymes and genes associated with intracellular survivability having different methylation patterns. To our knowledge, this is the first report about genome-wide methylation profiles of
strains and identification of a natural linear plasmid (15 kb) in this critical pathogen harboring methylated bases. The pan-genome analysis of 25
strains including two clinical strains revealed an open pan genome comprises of 7596 gene clusters. Likewise, structural variation analysis revealed that the genome of rough phenotype strain contains more insertions and deletions than the smooth phenotype and that of the reference strain. A total of 391 single nucleotide variations responsible for the non-synonymous mutations were detected in clinical strains compared to the reference genome. The comparative genomic analysis elucidates the genome plasticity in this emerging pathogen. Furthermore, the detection of genome-wide methylation profiles of
clinical strains may provide insight into the significant role of DNA methylation in pathogenicity and drug resistance in this opportunistic pathogen.
Significant propellant mass saving can be obtained with the use of complex multiple intermediate flyby maneuvers for conventional propulsion systems, and trip time also decreases for a portion of the ...proper solar sail missions. This paper discusses the performance of gravity assist （GA） in the time-optimal control problem of solar sailing with respect to sail lightness number and the energy difference between the initial and final orbit in the rendezvous problem in a two-body model, in which the GA is modeled as a substantial change in the velocity of the sailcraft at the GA time. In addition, this paper presents a method to solve the time-optimal problem of solar sailing with GA in a full ephemeris model, which introduces the third body＇s gravity in a dynamic equation. This study builds a set of inner constraints that can describe the GA process accurately. Finally, this study presents an example for evaluating the accuracy and rationality of the two-body model＇s simplification of GA by comparison with the full ephemeris model.
•Amikacin is only considered for multidrug-resistant tuberculosis (MDR-TB) treatment when a short MDR-TB regimen is designed.•The rrs mutations were found in 82% of amikacin-resistant isolates in ...southern China.•The A1401G mutation in the rrs gene was the most dominant mutation in amikacin-resistant isolates.•Analysis of rrs gene mutation will significantly reduce the time and cost to diagnose amikacin resistance.•Notably, 13.48% amikacin-resistant isolates had no known mutation in rrs, eis, tap and whiB7.
Amikacin is the only second-line injectable antituberculosis (anti-TB) drug still recommended for multidrug-resistant tuberculosis (MDR-TB) treatment when a short MDR-TB regimen is designed. Mutations in rrs and eis are reported to be associated with resistance to amikacin. In this study, we investigated the incidence of rrs, eis, tap and whiB7 mutations in amikacin-resistant Mycobacterium tuberculosis clinical isolates to find the proportion of different mutations related to amikacin resistance.
A total of 395 clinical isolates of M. tuberculosis were used for phenotypic drug susceptibility testing (DST) to 10 drugs with the Löwenstein–Jensen (L–J) method. We sequenced rrs, eis, tap and whiB7 genes in 178 M. tuberculosis clinical isolates (89 amikacin-resistant isolates and 89 of 306 amikacin-susceptible isolates).
Our data showed that 22.53% (89/395) M. tuberculosis clinical isolates were resistant to amikacin. Of the 89 amikacin-resistant isolates, 89.89% (80/89) were MDR-TB, of which 12.36% (11/89) were pre-extensively drug-resistant TB (pre–XDR-TB) and 77.53% (69/89) were XDR-TB. The rrs mutations were found in 82% (73/89) in amikacin-resistant M. tuberculosis clinical isolates. The A1401G alteration in the rrs gene was the most dominant mutation (80.90%; 72/89). Five mutations were detected as new in rrs, tap and whiB7. Notably, 13.48% (12/89) amikacin-resistant isolates had no known mutation in these genes.
Our data reveal that the rrs mutation is a predominant molecular marker of amikacin resistance in southern China. Analysis of the rrs gene mutations will significantly reduce the time and cost to diagnose amikacin resistance in TB patients. Other unknown amikacin resistance mechanism(s) exist.
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