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Tuberculosis (Edinburgh, Scotland) Jan 2022The prevalence of infections by nontuberculous mycobacteria is increasing, having surpassed tuberculosis in the United States and much of the developed world....
The prevalence of infections by nontuberculous mycobacteria is increasing, having surpassed tuberculosis in the United States and much of the developed world. Nontuberculous mycobacteria occur naturally in the environment and are a significant problem for patients with underlying lung diseases such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Current treatment regimens are lengthy, complicated, toxic and they are often unsuccessful as seen by disease recurrence. Mycobacterium abscessus is one of the most commonly encountered organisms in nontuberculous mycobacteria disease and it is the most difficult to eradicate. There is currently no systematically proven regimen that is effective for treating M. abscessus infections. Our approach to drug discovery integrates machine learning, medicinal chemistry and in vitro testing and has been previously applied to Mycobacterium tuberculosis. We have now identified several novel 1-(phenylsulfonyl)-1H-benzimidazol-2-amines that have weak activity on M. abscessus in vitro but may represent a starting point for future further medicinal chemistry optimization. We also address limitations still to be overcome with the machine learning approach for M. abscessus.
Topics: Antitubercular Agents; Bayes Theorem; Drug Discovery; Humans; Machine Learning; Mycobacterium abscessus
PubMed: 35077930
DOI: 10.1016/j.tube.2022.102168 -
Journal of Clinical Microbiology Oct 2023Macrolides, such as clarithromycin, are crucial in the treatment of nontuberculous mycobacteria (NTM). NTM are notoriously innately drug resistant, which has made the...
Macrolides, such as clarithromycin, are crucial in the treatment of nontuberculous mycobacteria (NTM). NTM are notoriously innately drug resistant, which has made the dependence on macrolides for their treatment even more important. Not surprisingly, resistance to macrolides has been documented in some NTM, including and , which are the two NTM species most often identified in clinical isolates. Resistance is mediated by point mutations in the 23S ribosomal RNA or by methylation of the rRNA by a methylase (encoded by an gene). Chromosomally encoded genes have been identified in many of the macrolide-resistant isolates, but not in . Now, Brown-Elliott et al. (J Clin Microbiol 61:e00428-23, 2023, https://doi.org/10.1128/JCM.00428-23) describe the identification of a new variant, (55) which was found either on the chromosome or on a plasmid in highly macrolide-resistant clinical isolates of . The chromosomal (55) gene appears to be associated with mobile elements; one gene is within a putative transposon and the second is in a large (37 kb) insertion/deletion. The plasmid carrying (55) also encodes type IV and type VII secretion systems, which are often linked on large mycobacterial plasmids and are hypothesized to mediate plasmid transfer. While the conjugative transfer of the (55)-containing plasmid between NTM has yet to be demonstrated, the inferences are clear, as evidenced by the dissemination of plasmid-mediated drug resistance in other medically important bacteria. Here, we discuss the findings of Brown-Elliott et al. and the potential ramifications on treatment of NTM infections.
Topics: Humans; Anti-Bacterial Agents; Mycobacterium chelonae; Macrolides; Drug Resistance, Bacterial; Clarithromycin; Mycobacterium; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Chromosomes
PubMed: 37724858
DOI: 10.1128/jcm.00628-23 -
International Journal of... 2023Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium... (Review)
Review
Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium tuberculosis (MTB), as well as nontuberculous mycobacteria such as the Mycobacterium abscessus complex (MABC) and Mycobacterium avium complex (MAC). Recently, new carbapenems and combinations of carbapenems with β-lactamase inhibitors have become available, but activity data in vitro against mycobacteria are so far scarce. Therefore, we performed a systematic review collating the minimum inhibitory concentrations (MICs) of carbapenems, with or without a β-lactamase inhibitors for MTB, MABC, and MAC. The databases PubMed and Web of Science were searched for the relevant articles in English up until September 21, 2022. Screening of studies was performed by two independent reviewers. MIC data by recommended methods with at least five individual MICs were included. Data were reported as MIC range, MIC, modal MIC, and/or histograms when individual MICs were available. The study protocol was registered at PROSPERO (CRD42021258537). After screening, a total of 75 studies with MIC data for carbapenems with or without β-lactamase inhibitors were included in the review. For MTB, the oral carbapenem tebipenem combined with the β-lactamase inhibitor clavulanic acid resulted in the most significant reduction of MICs. For MABC, the addition of avibactam to tebipenem resulted in a 64-fold reduction of modal MIC. Data were insufficient for the analysis of MAC. Carbapenems, and in particular the novel oral compound tebipenem, in combination with clavulanic acid for MTB and avibactam for MABC may be an untapped potential for difficult-to-treat mycobacterial infections.
Topics: Humans; beta-Lactamase Inhibitors; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium tuberculosis; Carbapenems; Penicillins; Clavulanic Acid; Microbial Sensitivity Tests; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous
PubMed: 37721224
DOI: 10.4103/ijmy.ijmy_131_23 -
Frontiers in Immunology 2021Autophagy is critically involved in host defense pathways through targeting and elimination of numerous pathogens autophagic machinery. Nontuberculous mycobacteria... (Review)
Review
Autophagy is critically involved in host defense pathways through targeting and elimination of numerous pathogens autophagic machinery. Nontuberculous mycobacteria (NTMs) are ubiquitous microbes, have become increasingly prevalent, and are emerging as clinically important strains due to drug-resistant issues. Compared to (Mtb), the causal pathogen for human tuberculosis, the roles of autophagy remain largely uncharacterized in the context of a variety of NTM infections. Compelling evidence suggests that host autophagy activation plays an essential role in the enhancement of antimicrobial immune responses and controlling pathological inflammation against various NTM infections. As similar to Mtb, it is believed that NTM bacteria evolve multiple strategies to manipulate and hijack host autophagy pathways. Despite this, we are just beginning to understand the molecular mechanisms underlying the crosstalk between pathogen and the host autophagy system in a battle with NTM bacteria. In this review, we will explore the function of autophagy, which is involved in shaping host-pathogen interaction and disease outcomes during NTM infections. These efforts will lead to the development of autophagy-based host-directed therapeutics against NTM infection.
Topics: Animals; Anti-Bacterial Agents; Autophagy; Biological Evolution; Drug Resistance, Bacterial; Host-Pathogen Interactions; Humans; Immunity, Innate; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria
PubMed: 34552591
DOI: 10.3389/fimmu.2021.728742 -
Central European Journal of Public... Mar 2022The aim of this study was to detect Mycobacterium tuberculosis complex, M. avium subsp. avium and M. intracellulare, Mycobacterium contamination and to explore the...
OBJECTIVES
The aim of this study was to detect Mycobacterium tuberculosis complex, M. avium subsp. avium and M. intracellulare, Mycobacterium contamination and to explore the aerosol transmission of mycobacteria in public buildings in China.
METHODS
A total of 552 environmental samples, namely 165 aerosol, 199 water, 70 air duct dust, and 118 soil samples, were collected from 39 public buildings and analysed using nested polymerase chain reaction.
RESULTS
The positivity rate of Mycobacterium tuberculosis complex, M. avium subsp. avium and M. intracellulare in air samples were 0.6% and 1.8%, respectively. There was significant difference in the positivity rate of Mycobacterium aerosol among the three types of public building (χ = 6.108, p = 0.047). No positive results of Mycobacterium tuberculosis complex and M. avium and M. intracellulare were obtained from cooling, tap, shower, or fountain water. The positivity rate of Mycobacterium for water samples was 31.7% (63/199). The positivity rate of Mycobacterium tuberculosis complex, M. avium subsp. avium and M. intracellulare, Mycobacterium in soil samples were 1.1%, 34.6% and 43.6%, respectively. There was significant difference in the positivity rate of M. avium and M. intracellulare (χ = 47.219, p < 0.001) and Mycobacterium (χ = 33.535, p < 0.001) in the different origins of soil samples.
CONCLUSIONS
Mycobacteria are widespread in public buildings. Mycobacterium tuberculosis complex, M. avium and M. intracellulare were simultaneously present in the air ducts of central air conditioning systems and indoor air in public buildings, which indicates that aerosol transmission is a potential route.
Topics: Aerosols; Humans; Mycobacterium; Mycobacterium avium Complex; Soil; Water
PubMed: 35421295
DOI: 10.21101/cejph.a5198 -
Journal of Medicinal Chemistry Apr 2023α-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC:...
α-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2)--(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against (MIC 6.25-12.5 μM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against , , , and . The sulfone derivatives exhibit lower MIC values (: 0.78 μM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of at 12.5 μM), while they are not cytotoxic against mammalian cell lines.
Topics: Animals; Amides; Anti-Bacterial Agents; Mammals; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis
PubMed: 37001025
DOI: 10.1021/acs.jmedchem.3c00009 -
Microbiology Spectrum Dec 2023represents the most common rapidly growing mycobacterial pathogen in cystic fibrosis and is extremely difficult to eradicate. Essential genes are required for growth,...
represents the most common rapidly growing mycobacterial pathogen in cystic fibrosis and is extremely difficult to eradicate. Essential genes are required for growth, often participate in pathogenesis, and encode valid drug targets for further chemotherapeutic developments. However, assessing the function of essential genes in remains challenging due to the limited spectrum of efficient genetic tools. Herein, we generated a Tet-OFF-based system allowing to knock down the expression of , encoding the mycolic acid transporter in mycobacteria. Using this conditional mutant, we confirm the essentiality of in planktonic cultures, in biofilms, and during infection in zebrafish embryos. Thus, in this study, we developed a robust and reliable method to silence the expression of any gene during host infection.
Topics: Animals; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Zebrafish; Mycobacterium; Gene Expression
PubMed: 37831478
DOI: 10.1128/spectrum.02836-23 -
BMC Veterinary Research Jan 2021Mycobacterium avium complex (MAC) causes a chronic infectious in the birds known as avian mycobacteriosis. Almost all species of the birds are susceptible to MAC which...
BACKGROUND
Mycobacterium avium complex (MAC) causes a chronic infectious in the birds known as avian mycobacteriosis. Almost all species of the birds are susceptible to MAC which consists of two closely related species of mycobacteria, that is, M. avium and M. intracellulare. This study aimed to determine the occurrence of Mycobacterium avium subsp. avium (MAA) in chickens and captive birds in selected states of Peninsular Malaysia.
RESULTS
A 300 fecal samples were collected from village chickens (n = 100), layer chickens (n = 100) and captive birds (n = 100). Fecal samples were split into two aliquots for microbiological and molecular detection of MAA. Microbiology detection consisted of microscopy (Ziehl-Neelsen staining) and culture of samples decontaminated with 1% Cetylperidinium chloride and vancomycin, nalidixic acid and amphotericin B (VNA) antibiotic cocktail [vancomycin (VAN) 100 μg/ml, nalidixic acid (NAL) 100 μg/ml and amphotericin B (AMB) 50 μg/ml] onto Löwenstein-Jensen (L-J). Molecular detection (PCR-IS901) was performed to detect MAA DNA from the feces and PCR-16S rRNA and IS901 for identification of genus Mycobacterium and Mycobacterium avium sub species avium isolated onto L-J. All samples (296) were AFB negative smear. M. avium was isolated in 0.3% (1/296) samples by culture and detected in 2.5% (6/242) samples by PCR (IS901). Other mycobacteria were found in 1.7% (5/296) chickens. Of five isolates, two were identified as Mycobacterium terrae and M. engbaekii and remaining isolates were not sequenced. Birds positive for M. avium included White Pelican (n = 1) Black Hornbill (n = 1), Macaw (n = 2), Cockatoo (n = 2) and village chicken (n = 1).
CONCLUSION
It is concluded that chickens and birds were infected with M. avium in selected areas of Peninsular Malaysia. Although, PCR is rapid, reliable and cost effective method for detection of M. avium in a subclinical stage, the culture of the avian feces should still be used as a reference test for the diagnosis of avian tuberculosis.
Topics: Animals; Birds; Chickens; DNA, Bacterial; Feces; Malaysia; Mycobacterium; Nontuberculous Mycobacteria; Polymerase Chain Reaction; RNA, Ribosomal, 16S; Tuberculosis, Avian
PubMed: 33413380
DOI: 10.1186/s12917-020-02695-8 -
Scientific Reports May 2021Microorganisms survive stresses by alternating the expression of genes suitable for surviving the immediate and present danger and eventually adapt to new conditions....
Microorganisms survive stresses by alternating the expression of genes suitable for surviving the immediate and present danger and eventually adapt to new conditions. Many bacteria have evolved a multiprotein "molecular machinery" designated the "Stressosome" that integrates different stress signals and activates alternative sigma factors for appropriate downstream responses. We and others have identified orthologs of some of the Bacillus subtilis stressosome components, RsbR, RsbS, RsbT and RsbUVW in several mycobacteria and we have previously reported mutual interactions among the stressosome components RsbR, RsbS, RsbT and RsbUVW from Mycobacterium marinum. Here we provide evidence that "STAS" domains of both RsbR and RsbS are important for establishing the interaction and thus critical for stressosome assembly. Fluorescence microscopy further suggested co-localization of RsbR and RsbS in multiprotein complexes visible as co-localized fluorescent foci distributed at scattered locations in the M. marinum cytoplasm; the number, intensity and distribution of such foci changed in cells under stressed conditions. Finally, we provide bioinformatics data that 17 (of 244) mycobacteria, which lack the RsbRST genes, carry homologs of Bacillus cereus genes rsbK and rsbM indicating the existence of alternative σ activation pathways among mycobacteria.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; Multiprotein Complexes; Mycobacterium marinum; Phosphoproteins; Phosphorylation; Sigma Factor; Signal Transduction; Stress, Physiological
PubMed: 33980893
DOI: 10.1038/s41598-021-89069-8 -
Emerging Infectious Diseases Mar 2021We analyzed 98 Mycobacterium tuberculosis complex isolates collected in 2 regions of Algeria in 2015-2018 from 93 cases of pulmonary tuberculosis. We identified 93/98...
We analyzed 98 Mycobacterium tuberculosis complex isolates collected in 2 regions of Algeria in 2015-2018 from 93 cases of pulmonary tuberculosis. We identified 93/98 isolates as M. tuberculosis lineage 4 and 1 isolate as M. tuberculosis lineage 2 (Beijing). We confirmed 4 isolates as M. bovis by whole-genome sequencing.
Topics: Algeria; Beijing; Humans; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis, Pulmonary
PubMed: 33622469
DOI: 10.3201/eid2703.191823