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International Journal of Medical... Mar 2024Mycobacteroides abscessus is one of the most resistant bacteria so far known and causes severe and hard to treat lung infections in predisposed patients such as those...
Mycobacteroides abscessus is one of the most resistant bacteria so far known and causes severe and hard to treat lung infections in predisposed patients such as those with Cystic Fibrosis (CF). Further, it causes nosocomial infections by forming biofilms on medical devices or water reservoirs. An eye-catching feature of M. abscessus is the growth in two colony morphotypes. Depending on the presence or absence of glycopeptidolipids on the cell surface, it forms smooth or rough colonies. In this study, a porous glass bead biofilm model was used to compare biofilm formation, biofilm organization and biofilm matrix composition in addition to the antimicrobial susceptibility of M. abscessus biofilms versus suspensions of isogenic (smooth and rough) patient isolates. Both morphotypes reached the same cell densities in biofilms. The biofilm architecture, however, was dramatically different with evenly distributed oligo-layered biofilms in smooth isolates, compared to tightly packed, voluminous biofilm clusters in rough morphotypes. Biofilms of both morphotypes contained more total biomass of the matrix components protein, lipid plus DNA than was seen in corresponding suspensions. The biofilm mode of growth of M. abscessus substantially increased resistance to the antibiotics amikacin and tigecycline. Tolerance to the disinfectant peracetic acid of both morphotypes was increased when grown as biofilm, while tolerance to glutaraldehyde was significantly increased in biofilm of smooth isolates only. Overall, smooth colony morphotypes had more pronounced antimicrobial resistance benefit when growing as biofilm than M. abscessus showing rough colony morphotypes.
Topics: Humans; Anti-Bacterial Agents; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Drug Resistance, Bacterial; Biofilms
PubMed: 38246090
DOI: 10.1016/j.ijmm.2024.151603 -
MSphere Feb 2024Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did...
UNLABELLED
Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did not prolong QT interval in animal model studies. This study evaluated the antibacterial activity of this novel compound against , , and and . The minimum inhibitory concentration (MIC) of WX-081 against three kinds of non-tuberculous mycobacteria (NTM) clinical strains was determined using microplate-based alamarBlue assay (MABA), and the antibacterial activity of WX-081 against NTM in J774A.1 cells and mice was evaluated. MIC ranges of WX-081 against clinical strains of and were 0.05-0.94 μg/mL, 0.88-7.22 μg/mL ( subsp. ), and 0.22-8.67 μg/mL ( subsp. ), respectively, which were slightly higher than those of BDQ. For , , and , WX-081 can reduce the intracellular bacterial load by 0.13-1.18, 0.18-1.50, and 0.17-1.03 log colony forming units (CFU)/mL, respectively, in a concentration-dependent manner. WX-081 has bactericidal activity against three NTM species in mice. WX-081 exhibited anti-NTM activity to the same extent as BDQ both and . WX-081 is a promising clinical candidate and should be studied further in clinical trials.
IMPORTANCE
Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of , , and during 2000-2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against , , and , in macrophages and mice, respectively.
Topics: Animals; Mice; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium chelonae; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Tuberculosis; Pyridines
PubMed: 38240581
DOI: 10.1128/msphere.00518-23 -
Microbiology Spectrum Feb 2024pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate...
pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate of resistance. Amikacin is critical to treatment, but the development of toxicity, amikacin resistance, and treatment failure are significant challenges. Amikacin has been characterized previously as peak-dependent and extended-interval dosing is commonly used. In our hollow fiber infection model of , amikacin exhibited time-dependent rather than the expected peak-dependent pharmacodynamics. Humanized amikacin exposures with more frequent, short-interval dosing (continuous infusion or every 12 hours) yielded improved microbiological response compared to extended-interval dosing (every 24 hours or 1-3 times per week). Short-interval dosing inhibited growth with a mean (SD) maximum Δlog colony forming units of -4.06 (0.52), significantly more than extended-interval dosing ( = 0.0013) every 24 hours, -2.40 (0.58), or 1-3 times per week, -2.39 (0.38). Growth recovery, an indicator of resistance emergence, occurred at 6.56 (0.70) days with short-interval dosing but was significantly earlier with extended-interval dosing ( = 0.0032) every 24 hours, 3.88 (0.85) days, and 1-3 times per week, 3.27 (1.72) days. Microbiological response correlated best with the pharmacodynamic index of %T > minimum inhibitory concentration (MIC), with an EC for growth inhibition of ~40%T > MIC. We used a previously published population model of amikacin to determine the probability of achieving 40%T > MIC and show that current dosing strategies are far below this target, which may partially explain why treatment failure remains so high for these infections. These data support a cautious approach to infrequent amikacin dosing for the treatment of .IMPORTANCEPulmonary disease caused by complex (MABSC) is increasing worldwide, particularly in patients with cystic fibrosis. MABSC is challenging to treat due to high levels of antibiotic resistance. Treatment requires 2-4 antibiotics over more than 12 months and has a significant risk of toxicity but still fails to eradicate infection in over 50% of patients with cystic fibrosis. Antibiotic dosing strategies have been largely informed by common bacteria such as . The "pharmacodynamic" effects of amikacin, a backbone of MABSC treatment, were thought to be related to maximum "peak" drug concentration, leading to daily or three times weekly dosing. However, we found that amikacin MABSC kill and growth recovery, an indicator of antibiotic resistance, are dependent on how long amikacin concentrations are above the minimum inhibitory concentration, not how high the peak concentration is. Therefore, we recommend a re-evaluation of amikacin dosing to determine if increased frequency can improve efficacy.
Topics: Humans; Amikacin; Mycobacterium abscessus; Cystic Fibrosis; Anti-Bacterial Agents; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous
PubMed: 38236037
DOI: 10.1128/spectrum.03222-23 -
ERJ Open Research Jan 2024https://bit.ly/3QwLQ8T.
https://bit.ly/3QwLQ8T.
PubMed: 38226066
DOI: 10.1183/23120541.00610-2023 -
The Journal of Biological Chemistry Feb 2024The FF-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis...
The FF-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the F domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem-avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307-tebipenem-avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.
Topics: Humans; Adenosine Triphosphate; Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Enzyme Inhibitors; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Diarylquinolines
PubMed: 38176652
DOI: 10.1016/j.jbc.2023.105618 -
Cureus Dec 2023Cosmetic surgeries are very popular and glamorized by the mainstream media and celebrities. Many individuals perceive certain bodily features as appealing for physical...
Cosmetic surgeries are very popular and glamorized by the mainstream media and celebrities. Many individuals perceive certain bodily features as appealing for physical attraction and will attempt to obtain these features by surgery. However, these surgeries are not without risk, and significant consequences can occur if not performed by qualified medical professionals under sterile procedures. The authors present novel cases of two healthy young female patients who underwent a Brazilian butt lift (BBL) procedure a week apart by the same plastic surgeon in Mexico and developed dark painful lesions secondary to (), a multidrug-resistant non-tuberculous mycobacterium (NTM). The literature review shows a paucity of data concerning NTM infections via surgical procedures of this type. The first case was of a 31-year-old woman who underwent a BBL and presented with bilateral dark painful buttock lesions weeks later. The patient returned to the plastic surgeon, who drained some lesions and prescribed oral antibiotics. The patient's clinical status continued to deteriorate and presented to the hospital for further assessment. The patient was initially started on broad-spectrum antibiotic therapy. The patient was found to have an HIV infection with a relatively preserved CD4 lymphocyte count and was started on antiretroviral therapy (ART). Intraoperative excisional tissue sample cultures grew . The patient was started on empiric tigecycline, cefoxitin, and linezolid. Preliminary culture susceptibilities showed resistance to linezolid. Linezolid was discontinued, amikacin was started, and cefoxitin and tigecycline were continued. Tigecycline, cefoxitin, and amikacin were continued and final susceptibilities showed sensitivity to the current treatment. The patient received a total of four months of treatment with tigecycline, cefoxitin, and amikacin. The second case was of a 28-year-old woman who underwent a BBL a week after the first patient by the same surgeon and developed multiple gluteal and body abscesses. The patient underwent bilateral thigh and gluteal, right chest wall, and breast surgical debridements with intraoperative cultures at a different hospital facility, which grew . Susceptibilities were not performed there. The patient was transferred to our facility for further care. Intraoperative cultures remained negative, and the patient was treated with a six-month course of tigecycline, cefoxitin, and amikacin.
PubMed: 38174196
DOI: 10.7759/cureus.49881 -
European Journal of Medicinal Chemistry Feb 2024Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M....
Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M. abscessus (Mab) has evolved several countermeasures to scavenge iron from host carrier proteins, including the production of siderophores, which play a crucial role in these processes. In this study, we solved, for the first time, the crystal structure of Mab-SaS, the first enzyme involved in the biosynthesis of siderophores. Moreover, we screened a small, focused library and identified a compound exhibiting a potent inhibitory effect against Mab-SaS (IC ≈ 2 μM). Its binding mode was investigated by means of Induced Fit Docking simulations, performed on the crystal structure presented herein. Furthermore, cytotoxicity data and pharmacokinetic predictions revealed the safety and drug-likeness of this class of compounds. Finally, the crystallographic data were used to optimize the model for future virtual screening campaigns. Taken together, the findings of our study pave the way for the identification of potent Mab-SaS inhibitors, based on both established and unexplored chemotypes.
Topics: Humans; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Salicylates; Siderophores; Iron
PubMed: 38169270
DOI: 10.1016/j.ejmech.2023.116073 -
Proceedings of the National Academy of... Jan 2024(), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor...
(), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Δ in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Δ. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti- antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for and other NTM infections.
Topics: Humans; Animals; Mice; Mycobacterium abscessus; Spectinomycin; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Nontuberculous Mycobacteria; Anti-Infective Agents; Ethylenes; Microbial Sensitivity Tests
PubMed: 38165935
DOI: 10.1073/pnas.2314101120 -
GeoHealth Jan 2024Nontuberculous mycobacteria (NTM) are environmentally acquired opportunistic pathogens that can cause chronic lung disease. Within the U.S., Hawai'i shows the highest...
Nontuberculous mycobacteria (NTM) are environmentally acquired opportunistic pathogens that can cause chronic lung disease. Within the U.S., Hawai'i shows the highest prevalence rates of NTM lung infections. Here, we investigated a potential role for active volcanism at the Kīlauea Volcano located on Hawai'i Island in promoting NTM growth and diversity. We recovered NTM that are known to cause lung disease from plumbing biofilms and soils collected from the Kīlauea environment. We also discovered viable , and subsp. on volcanic ash collected during the 2018 Kīlauea eruption. Analysis of soil samples showed that NTM prevalence is positively associated with bulk content of phosphorus, sulfur, and total organic carbon. In growth assays, we showed that phosphorus utilization is essential for proliferation of Kīlauea-derived NTM, and demonstrate that NTM cultured with volcanic ash adhere to ash surfaces and remain viable. Ambient dust collected on O'ahu concurrent with the 2018 eruption contained abundant fresh volcanic glass, suggestive of inter-island ash transport. Phylogenomic analyses using whole genome sequencing revealed that Kīlauea-derived NTM are genetically similar to respiratory isolates identified on other Hawaiian Islands. Consequently, we posit that volcanic eruptions could redistribute environmental microorganisms over large scales. While additional studies are needed to confirm a direct role of ash in NTM dispersal, our results suggest that volcanic particulates harbor and can redistribute NTM and should therefore be studied as a fomite for these burgeoning, environmentally acquired respiratory infections.
PubMed: 38161597
DOI: 10.1029/2023GH000889 -
Tuberkuloz Ve Toraks Dec 2023Non-tuberculous mycobacteria (NTM) can cause diseases not only in individuals with compromised immune systems but also in those with normal immune function. This study...
Non-tuberculous mycobacteria (NTM) can cause diseases not only in individuals with compromised immune systems but also in those with normal immune function. This study aimed to compare the prevalence of NTM in Türkiye and worldwide between 2012 and 2022. This study was designed following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) procedure. A systematic search was conducted between January 2012 and September 2022 using different electronic databases, including Pubmed, Medline, Embase, Web of Science, Ebsco, Scopus, Türk Medline, and Google Scholar. During the literature review process, titles and abstracts were examined and the full texts of the studies were accessed. In 13 research articles from Türkiye included in the study, a total of 17.293 samples were studied and a total of 1304 NTM (7.54%) strains were isolated from these samples. Among the 1304 NTM strains reported from Türkiye, the top three most frequently isolated species were M. abscessus (29.83%), M. lentiflavum (14.97%), M. fortuitum (14.38%). In 35 studies included from around the world, a total of 512.626 samples were studied and a total of 12.631 NTM (2.46%) strains were isolated from these samples. Among the 12631 NTM strains isolated, the top three most frequently isolated species were M. intracellulare (28.13%), M. avium (17.70%) and M. abscessus (14.88%). This study unveiled the global prevalence of NTM-infected patients, detailing species distribution and microbiological diagnostic methods. Variations in NTM spread were observed, influenced by diverse factors.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Prevalence; Turkey
PubMed: 38152011
DOI: 10.5578/tt.20239609