Some naturally occurring compounds, known for their antimicrobial activities, have been employed as food additives. However, their efficacy in treating infections caused by antibiotic-resistant bacteria is yet to be fully explored. Rapidly growing mycobacteria (RGM), a category within nontuberculous mycobacteria (NTM), are prevalent in various environments and can lead to infections in humans. The rise of antimicrobial resistance within RGM is a documented concern. In this study, we reported that four specific natural compounds effectively inhibited the growth and biofilm formation of three key RGM pathogens M. abscessus, M. fortuitum, and M. chelonae. We screened 12 natural compounds for their effectiveness against antibiotic-resistant clinical strains of RGM. Four compounds showed significant inhibitory effects from the most effective to least: trans-cinnamaldehyde, carvacrol, gentisaldehyde, and phloroglucinaldehyde. In the analysis of time-killing kinetics, gentisaldehyde and phloroglucinaldehyde displayed bactericidal activity while trans-cinnamaldehyde and carvacrol exhibited bacteriostatic effects. At 1× minimal inhibition concentrations, these compounds significantly reduced biofilm formation in all three RGM species to levels between 2.9% and 20.5% relative to controls. Checkerboard assays indicated synergistic interactions between these four compounds and antibiotics such as amikacin, clarithromycin, and linezolid. Of these 12 compound-antibiotic combinations, the pairs of carvacrol-linezolid, carvacrol-amikacin, and gentisaldehyde-clarithromycin demonstrated the most synergy against multiple RGM strains. Moreover, two other compounds citral and geraniol showed synergism with all three test antibiotics. Time-killing assays further confirmed most of synergistic combinations identified in the checkerboard tests. Our research suggests the potential of these essential oils and phenolic aldehydes, both individually and in combination with antibiotics, in treating RGM infections. In addition, this work illuminates applications of these natural compounds in environmental remediation to mitigate bacterial persistence for the control of infectious diseases.
OBJECTIVE: The emergence of antimicrobial resistance within rapidly growing mycobacteria (RGM) poses a significant threat to public health. This study investigates the potential of naturally occurring compounds to combat infections caused by antibiotic-resistant RGM including M. abscessus, M. fortuitum, and M. chelonae. We identified four specific natural compounds showing impressive inhibitory effects against antibiotic-resistant clinical strains. These compounds not only inhibited the growth and biofilm formation but also exhibited synergistic interactions with antibiotics against key RGM pathogens. Our findings highlight the alternative treatment strategies for RGM infections and potential environmental applications of these natural compounds in mitigating microbial persistence and controlling infectious diseases.

暂无摘要。

Mycobacterium abscessus (M. abscessus) is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 μM against M. abscessus type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against M. abscessus were identified. Among them, bithionol, a clinically approved antiparasitic agent, showed excellent antibacterial activity and inhibited the growth of three different subtypes of M. abscessus from 0.625 μM to 2.5 μM. We confirmed the bactericidal activity of bithionol by the MBC/MIC ratio being ≤4 and the time-kill curve study and also electron microscopy study. Interestingly, it was found that at 128 μg/mL, bithionol could completely eliminate biofilms after 48h, demonstrating an outstanding antibiofilm capability compared to commonly used antibiotics. Additionally, bithionol could eliminate 99.9% of biofilm bacteria at 64 μg/mL, 99% at 32 μg/mL, and 90% at 16 μg/mL. Therefore, bithionol may be a potential candidate for the treatment of M. abscessus infections due to its significant antimicrobial and antibiofilm activities.

BACKGROUND: Microbiological diagnosis of mycobacteriosis is often difficult, as it is necessary to differentiate between transient colonization and active infection.
METHODS: We studied the cultural properties of Mycobacterium abscessus complex (MABSc) strains obtained from cystic fibrosis patients, and also analyzed composite correlation index (CCI) values in patients with repeated MABSc inoculation and their correlation with the presence of clinical and radiological manifestations of mycobacteriosis.
RESULTS: As a result, MABSc more often grew in S-form colonies in patients without clinical manifestations of chronic infection, while R-form colonies were characteristic of patients with chronic infection and clinical symptoms. At the same time, in patients examined once, no growth of colonies in the R-form was recorded, and all strains produced growth in the form of either S-colonies or in the S- and R-forms simultaneously. Statistically significant results were obtained for the relationship of the CCI with the clinical and radiological picture. In addition, a heterogeneous MABSc population with low CCI score values correlated with the development of mycobacteriosis in patients. In patients with high CCI score values (homogeneity of isolated strains), on the contrary, there were no radiological or clinical signs of the disease.
CONCLUSIONS: These data make it possible to build a strategy for monitoring patients depending on changes in CCI score values. The use of CCI matrix to evaluate microorganisms\' identification results is a potentially new method that expands the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

Aim: The WHO, Global tuberculosis report 2022 estimated number of tuberculosis (TB) cases reached 10.6 million in 2021, reflecting a 4.5% increase compared with the 10.1 million reported in 2020. The incidence rate of TB showed 3.6% rise from 2020 to 2021. Results/methodology: This manuscript discloses Cu-promoted single pot A3-coupling between triclosan (TCS)-based alkyne, formaldehyde and secondary amines to yield TCS-based Mannich adducts. Additionally, the coupling of TCS-alkynes in the presence of Cu(OAc)2 afforded the corresponding homodimers. Among tested compounds, the most potent one in the series 11 exhibited fourfold higher potency than rifabutin against drug-resistant Mycobacterium abscessus. The selectivity index was also substantially improved, being 26 (day 1) and 15 (day 3), which is four-times better than TCS.
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暂无摘要。

Non-Tuberculous mycobacteria (NTM) are opportunistic environmental bacteria. Globally, NTM incidence is increasing and modeling suggests that, without new interventions, numbers will continue to rise. Effective treatments for NTM infections remain suboptimal. Standard therapy for Mycobacterium avium complex, the most commonly isolated NTM, requires a 3-drug regime taken for approximately 18 months, with rates of culture conversion reported between 45 and 70%, and high rates of relapse or reinfection at up to 60%. New therapeutic options for NTM treatment are urgently required. A survey of ongoing clinical trials for new NTM therapy listed on ClinicalTrials.Gov using the terms \'Mycobacterium avium\', \'Mycobacterium abscessus\', \'Mycobacterium intracellulare\', \'Non tuberculous Mycobacteria\' and \'Nontuberculous Mycobacteria\' and a selection criterion of interventional studies using antibiotics demonstrates that most trials involve dose and combination therapy of the guideline based therapy or including one or more of; Amikacin, Clofazimine, Azithromycin and the anti-TB drugs Bedaquiline and Linezolid. The propensity of NTMs to form biofilms, their unique cell wall and expression of both acquired and intrinsic resistance, are all hampering the development of new anti-NTM therapy. Increased investment in developing targeted treatments, specifically for NTM infections is urgently required.

Although clofazimine is currently one of the standard regimens for Mycobacterium abscessus, it frequently causes skin discoloration, posing esthetic concerns for patients. We studied thirteen Asian patients with pulmonary nontuberculous mycobacterial disease treated with clofazimine at the NHO Kinki Chuo Chest Medical Center. In three patients (two women and one man) whose dosing regimens were altered owing to skin discoloration, we continuously measured luminance (L*), red-green (a*), and yellow-blue (b*) values (using a colorimeter) in both sun-exposed and sun-unexposed skin areas at each visit. Compared to baseline L* and a* values, the ΔL* values were negative (decreased brightness) and Δa* values were positive (increased redness) while patients received daily clofazimine. After switching to intermittent or reduced dosing, these changes gradually diminished. If such a dose reduction does not affect the therapeutic outcome, an even lower clofazimine dose may be attempted to minimize skin adverse effects.

BACKGROUND: From June 2021 to July 2021, our hospital confirmed 3 cases of Mycobacterium infection in skin abscesses. All 3 patients underwent thread embedding and weight loss surgery at the same informal beauty institution, with a history of silk protein injection. None of the patients had any other underlying diseases or surgical history. Symptoms and signs show that the disease is acute and the course of the disease is short. All patients have found subcutaneous masses in different parts of the body. In most cases, the masses show redness and swelling, and some of the masses are accompanied by tenderness, wave sensation, and rupture. After some of the masses rupture, purulent secretions can be seen.
METHODS: The pus secreted by the skin lesions of the three patients were cultured to a single bacterium, which was identified by MALDI-TOF MS. Multiple locus sequence typing (MLST) was performed using three specific genes (hsp65, rpoB, and secA1) and seven housekeeping genes (argH, cya, glpK, gnd, murC, pta, and purH). The results were queried through the MLST database of Mycobacterium abscess.
RESULTS: All three strains of bacteria were Mycobacterium abscess type ST279 massiliense subtype. Three antibacterial drugs including cefmetazole, amikacin, and clarithromycin were administered in combination with 5-aminolevulinic acid photodynamic therapy (ALA-PDT). After 3 - 6 months, there was no obvious redness or swelling in the surrounding tissues of the wound, and no obvious purulent secretions were observed. All patients were cured and discharged from the hospital. After a follow-up of six months, there was no recurrence of the lesions.
CONCLUSIONS: Medical institutions must strictly follow infection control guidelines and take preventive measures to prevent such incidents from happening again. ALA-PDT as a combination therapy for nontuberculous Mycobacterium (NTM) skin infections can improve treatment efficacy and shorten antibiotic usage time.

Mycobacterium abscessus (Mab) is an opportunistic pathogen afflicting individuals with underlying lung disease such as Cystic Fibrosis (CF) or immunodeficiencies. Current treatment strategies for Mab infections are limited by its inherent antibiotic resistance and limited drug access to Mab in its in vivo niches resulting in poor cure rates of 30-50%. Mab\'s ability to survive within macrophages, granulomas and the mucus laden airways of the CF lung requires adaptation via transcriptional remodeling to counteract stresses like hypoxia, increased levels of nitrate, nitrite, and reactive nitrogen intermediates. Mycobacterium tuberculosis (Mtb) is known to coordinate hypoxic adaptation via induction of respiratory nitrate assimilation through the nitrate reductase narGHJI. Mab, on the other hand, does not encode a respiratory nitrate reductase. In addition, our recent study of the transcriptional responses of Mab to hypoxia revealed marked down-regulation of a locus containing putative nitrate assimilation genes, including the orphan response regulator nnaR (nitrate/nitrite assimilation regulator). These putative nitrate assimilation genes, narK3 (nitrate/nitrite transporter), nirBD (nitrite reductase), nnaR, and sirB (ferrochelatase) are arranged contiguously while nasN (assimilatory nitrate reductase identified in this work) is encoded in a different locus. Absence of a respiratory nitrate reductase in Mab and down-regulation of nitrogen metabolism genes in hypoxia suggest interplay between hypoxia adaptation and nitrate assimilation are distinct from what was previously documented in Mtb. The mechanisms used by Mab to fine-tune the transcriptional regulation of nitrogen metabolism in the context of stresses e.g. hypoxia, particularly the role of NnaR, remain poorly understood. To evaluate the role of NnaR in nitrate metabolism we constructed a Mab nnaR knockout strain (MabΔnnaR ) and complement (MabΔnnaR+C ) to investigate transcriptional regulation and phenotypes. qRT-PCR revealed NnaR is necessary for regulating nitrate and nitrite reductases along with a putative nitrate transporter. Loss of NnaR compromised the ability of Mab to assimilate nitrate or nitrite as sole nitrogen sources highlighting its necessity. This work provides the first insights into the role of Mab NnaR setting a foundation for future work investigating NnaR\'s contribution to pathogenesis.