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PloS One 2023Mycobacterium ulcerans disease is a necrotising disease of the skin and subcutaneous tissue and is effectively treated with eight-weeks antibiotic therapy. Significant...
Mycobacterium ulcerans disease is a necrotising disease of the skin and subcutaneous tissue and is effectively treated with eight-weeks antibiotic therapy. Significant toxicities, however, are experienced under this prolonged regimen. Here, we investigated the length of antibiotic duration required to achieve negative cultures of M. ulcerans disease lesions and evaluated the influence of patient characteristics on this outcome. M. ulcerans cases from an observational cohort that underwent antibiotic treatment prior to surgery and had post-excision culture assessment at Barwon Health, Victoria, from May 25 1998 to June 30 2019, were included. Antibiotic duration before surgery was grouped as <2 weeks, ≥2-<4 weeks, ≥4-<6 weeks, ≥6-<8 weeks, ≥8-<10 weeks and ≥10-20 weeks. Cox regression analyses were performed to assess the association between variables and culture positive results. Ninety-two patients fitted the inclusion criteria. The median age was 60 years (IQR 28-74.5) and 51 (55.4%) were male. Rifampicin-based regimens were predominantly used in combination with clarithromycin (47.8%) and ciprofloxacin (46.7%), and the median duration of antibiotic treatment before surgery was 23 days (IQR, 8.0-45.5). There were no culture positive results after 19 days of antibiotic treatment and there was a significant association between antibiotic duration before surgery and a culture positive outcome (p<0.001). The World Health Organisation category of the lesion and the antibiotic regimen used had no association with the culture outcome. Antibiotics appear to be effective at achieving negative cultures of M. ulcerans disease lesions in less than the currently recommended eight-week duration.
Topics: Humans; Male; Middle Aged; Female; Anti-Bacterial Agents; Mycobacterium ulcerans; Cohort Studies; Buruli Ulcer; Treatment Outcome
PubMed: 37093836
DOI: 10.1371/journal.pone.0284201 -
ELife Apr 2023Buruli ulcer (BU) is a neglected tropical disease caused by infection of subcutaneous tissue with . BU is commonly reported across rural regions of Central and West...
BACKGROUND
Buruli ulcer (BU) is a neglected tropical disease caused by infection of subcutaneous tissue with . BU is commonly reported across rural regions of Central and West Africa but has been increasing dramatically in temperate southeast Australia around the major metropolitan city of Melbourne, with most disease transmission occurring in the summer months. Previous research has shown that Australian native possums are reservoirs of and that they shed the bacteria in their fecal material (excreta). Field surveys show that locales where possums harbor overlap with human cases of BU, raising the possibility of using possum excreta surveys to predict the risk of disease occurrence in humans.
METHODS
We thus established a highly structured 12 month possum excreta surveillance program across an area of 350 km in the Mornington Peninsula area 70 km south of Melbourne, Australia. The primary objective of our study was to assess using statistical modeling if surveillance of possum excreta provided useful information for predicting future human BU case locations.
RESULTS
Over two sampling campaigns in summer and winter, we collected 2,282 possum excreta specimens of which 11% were PCR positive for -specific DNA. Using the spatial scanning statistical tool , we observed non-random, co-correlated clustering of both positive possum excreta and human BU cases. We next trained a statistical model with the Mornington Peninsula excreta survey data to predict the future likelihood of human BU cases occurring in the region. By observing where human BU cases subsequently occurred, we show that the excreta model performance was superior to a null model trained using the previous year's human BU case incidence data (AUC 0.66 vs 0.55). We then used data unseen by the excreta-informed model from a new survey of 661 possum excreta specimens in Geelong, a geographically separate BU endemic area to the southwest of Melbourne, to prospectively predict the location of human BU cases in that region. As for the Mornington Peninsula, the excreta-based BU prediction model outperformed the null model (AUC 0.75 vs 0.50) and pinpointed specific locations in Geelong where interventions could be deployed to interrupt disease spread.
CONCLUSIONS
This study highlights the nature of BU by confirming a quantitative relationship between possum excreta shedding of and humans developing BU. The excreta survey-informed modeling we have described will be a powerful tool for the efficient targeting of public health responses to stop BU.
FUNDING
This research was supported by the National Health and Medical Research Council of Australia and the Victorian Government Department of Health (GNT1152807 and GNT1196396).
Topics: Humans; Australia; Bacterial Shedding; Bacterial Zoonoses; Buruli Ulcer; Disease Reservoirs; Feces; Models, Statistical; Mycobacterium ulcerans; Phalangeridae
PubMed: 37057888
DOI: 10.7554/eLife.84983 -
Future Science OA Mar 2023is the causative agent of Buruli ulcer - a necrotizing skin infection. As an environmental pathogen, it has developed stress response mechanisms for survival. Similar... (Review)
Review
is the causative agent of Buruli ulcer - a necrotizing skin infection. As an environmental pathogen, it has developed stress response mechanisms for survival. Similar to endospore formation in , it is likely that employs sporulation mechanisms for its survival and transmission. In this review, we modeled possible transmission routes and patterns of from the environment to its host. We provided insights into the evolution of and its genomic profiles. We discuss reservoirs of as an environmental pathogen and its environmental survival. We comprehensively discuss sporulation as a possible stress response mechanism and modelled endospore formation in . At last, we highlighted sporulation associated markers, which upon expression trigger endospore formation.
PubMed: 37026027
DOI: 10.2144/fsoa-2022-0044 -
Impact of Temperature and Oxygen Availability on Gene Expression Patterns of Mycobacterium ulcerans.Microbiology Spectrum Mar 2023Buruli ulcer disease is a neglected tropical disease caused by the environmental pathogen Mycobacterium ulcerans. The M. ulcerans major virulence factor is mycolactone,...
Buruli ulcer disease is a neglected tropical disease caused by the environmental pathogen Mycobacterium ulcerans. The M. ulcerans major virulence factor is mycolactone, a lipid cytotoxic compound whose genes are carried on a plasmid. Although an exact reservoir and mode(s) of transmission are unknown, data provide evidence of both. First, Buruli ulcer incidence and M. ulcerans presence have been linked to slow-moving water with low oxygen. M. ulcerans has also been suggested to be sensitive to UV due to termination in , encoding a phytoene dehydrogenase, required for carotenoid production. Further, M. ulcerans has been shown to cause disease following puncture but not when introduced to open abrasion sites, suggesting that puncture is necessary for transmission and pathology. Despite these findings, the function and modulation of mycolactone and other genes in response to dynamic abiotic conditions such as UV, temperature, and oxygen have not been shown. In this study, we investigated modulation of mycolactone and other genes on exposure to changing UV and oxygen microenvironmental conditions. Mycolactone expression was downregulated on exposure to the single stress high temperature and did not change significantly with exposure to UV; however, it was upregulated when exposed to microaerophilic conditions. Mycolactone expression was downregulated under combined stresses of high temperature and low oxygen, but there was upregulation of several stress response genes. Taken together, results suggest that temperature shapes M. ulcerans metabolic response more so than UV exposure or oxygen requirements. These data help to define the environmental niche of M. ulcerans and metabolic responses during initial human infection. Buruli ulcer is a debilitating skin disease caused by the environmental pathogen Mycobacterium ulcerans. M. ulcerans produces a toxic compound, mycolactone, which leads to tissue necrosis and ulceration. Barriers to preventing Buruli ulcer include an incomplete understanding of M. ulcerans reservoirs, how the pathogen is transmitted, and under what circumstances mycolactone and other M. ulcerans genes are expressed and produced in its natural environment and in the host. We conducted a study to investigate M. ulcerans gene expression under several individual or combined abiotic conditions. Our data showed that mycolactone expression was downregulated under combined stresses of high temperature and low oxygen but there was upregulation of several stress response genes. These data are among only a few studies measuring modulation of mycolactone and other M. ulcerans genes that could be involved in pathogen fitness in its natural environment and virulence while within the host.
PubMed: 36912651
DOI: 10.1128/spectrum.04968-22 -
BioRxiv : the Preprint Server For... Feb 2023The drivers of tissue necrosis in infection (Buruli ulcer disease) have historically been ascribed solely to the directly cytotoxic action of the diffusible exotoxin,...
The drivers of tissue necrosis in infection (Buruli ulcer disease) have historically been ascribed solely to the directly cytotoxic action of the diffusible exotoxin, mycolactone. However, its role in the clinically-evident vascular component of disease aetiology remains poorly explained. We have now dissected mycolactone's effects on primary vascular endothelial cells and . We show that mycolactone-induced changes in endothelial morphology, adhesion, migration, and permeability are dependent on its action at the Sec61 translocon. Unbiased quantitative proteomics identified a profound effect on proteoglycans, driven by rapid loss of type II transmembrane proteins of the Golgi, including enzymes required for glycosaminoglycan (GAG) synthesis, combined with a reduction in the core proteins themselves. Loss of the glycocalyx is likely to be of particular mechanistic importance, since knockdown of galactosyltransferase II (beta-1,3-galactotransferase 6; B3Galt6), the GAG linker-building enzyme, phenocopied the permeability and phenotypic changes induced by mycolactone. Additionally, mycolactone depleted many secreted basement membrane components and microvascular basement membranes were disrupted . Remarkably, exogenous addition of laminin-511 reduced endothelial cell rounding, restored cell attachment and reversed the defective migration caused by mycolactone. Hence supplementing mycolactone-depleted extracellular matrix may be a future therapeutic avenue, to improve wound healing rates.
PubMed: 36865118
DOI: 10.1101/2023.02.21.529382 -
Antibiotics (Basel, Switzerland) Feb 2023() causes tuberculosis-like lung infection in both immunocompetent and immunocompromised patients. Current standard therapy against infection is lengthy and difficult...
() causes tuberculosis-like lung infection in both immunocompetent and immunocompromised patients. Current standard therapy against infection is lengthy and difficult to adhere to. Although β-lactams are the most important class of antibiotics, representing 65% of the global antibiotic market, they have been traditionally dismissed for the treatment of mycobacterial infections, as they were considered inactive against mycobacteria. A renewed interest in β-lactams as antimycobacterial agents has shown their activity against several mycobacterial species, including , or ; however, information against is lacking. In this study, we determined the in vitro activity of several β-lactams against . A selection of 32 agents including all β-lactam chemical classes (penicillins, cephalosporins, carbapenems and monobactams) with three β-lactamase inhibitors (clavulanate, tazobactam and avibactam) were evaluated against 22 strains by MIC assays. Penicillins plus clavulanate and first- and third-generation cephalosporins were the most active β-lactams against . Combinatorial time-kill assays revealed favorable interactions of amoxicillin-clavulanate and cefadroxil with first-line treatment. Amoxicillin-clavulanate and cefadroxil are oral medications that are readily available, and well tolerated with an excellent safety and pharmacokinetic profile that could constitute a promising alternative option for therapy.
PubMed: 36830246
DOI: 10.3390/antibiotics12020335 -
NIHR Open Research 2022Buruli ulcer (BU) can lead to disfiguring ulcers and permanent disability. The 2030 World Health Organization (WHO) road map for Neglected Tropical Diseases (NTDs) calls...
Buruli-RifDACC: Evaluation of the efficacy and cost-effectiveness of high-dose versus standard-dose rifampicin on outcomes in disease, a protocol for a randomised controlled trial in Ghana.
BACKGROUND
Buruli ulcer (BU) can lead to disfiguring ulcers and permanent disability. The 2030 World Health Organization (WHO) road map for Neglected Tropical Diseases (NTDs) calls for major scaling up in diagnosis and management to eliminate disability due to the disease. Current treatment for BU is with daily oral rifampicin (10mg/kg dose) and clarithromycin (15mg/kg dose) for eight weeks, combined with standard gauze wound dressings. Dialkylcarbamoyl chloride (DACC)-coated dressings have been shown to irreversibly bind bacteria on wound surfaces resulting in their removal when dressings are changed. This trial aims to determine whether combining a high-dose oral rifampicin regimen with DACC dressings can improve the rate of wound healing relative to standard-dose oral rifampicin combined with DACC dressings.
METHODS
This is an individual, multi-centre Phase 3 randomised controlled trial, which will be conducted in three clinical sites in Ghana. The primary outcome measure will be the mean time to clearance of viable mycobacteria. Cost and health-related quality of life data will be collected, and a cost-effectiveness analysis will be performed.
DISCUSSION
The findings from this trial could lead to a change in how BU is treated. A shorter but more efficacious regimen would lead to improved treatment outcomes and potentially substantial financial and economic savings.
TRIAL REGISTRATION
Pan African Clinical Trials Repository (registration number; PACTR202011867644311). Registered on 30 November 2020.
PubMed: 36825217
DOI: 10.3310/nihropenres.13332.2 -
Journal of Infection and Chemotherapy :... May 2023Buruli ulcer is the third most common mycobacterial infection worldwide and is mainly diagnosed in tropical regions. Globally, this progressive disease is caused by...
Buruli ulcer is the third most common mycobacterial infection worldwide and is mainly diagnosed in tropical regions. Globally, this progressive disease is caused by Mycobacterium ulcerans; however, Mycobacterium ulcerans subsp. shinshuense, an Asian variant, has been exclusively identified in Japan. Because of insufficient clinical cases, the clinical features of M. ulcerans subsp. shinshuense-associated Buruli ulcer remain unclear. A 70-year-old Japanese woman presented with erythema on her left backhand. The skin lesion deteriorated without an apparent etiology of inflammation, and she was referred to our hospital 3 months after disease onset. A biopsy specimen was incubated in 2% Ogawa medium at 30 °C. After 66 days, we detected small yellow-pigmented colonies, suggesting scotochromogens. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI Biotyper; Bruker Daltonics, Billerica, MA, USA) indicated that the organism was Mycobacterium pseudoshottsii or Mycobacterium marinum. However, additional PCR testing for the insertion sequence 2404 (IS2404) was positive, suggesting that the pathogen was either M. ulcerans or M. ulcerans subsp. shinshuense. Further examination by 16S rRNA sequencing analysis, focusing on nucleotide positions 492, 1247, 1288, and 1449-1451, we finally identified the organism as M. ulcerans subsp. shinshuense. The patient was successfully treated with 12 weeks of clarithromycin and levofloxacin treatment. Mass spectrometry is the latest microbial diagnostic method; however, it cannot be used to identify M. ulcerans subsp. shinshuense. To accurately detect this enigmatic pathogen and uncover its epidemiology and clinical characteristics in Japan, more accumulation of clinical cases with accurate identification of the causative pathogen is essential.
Topics: Humans; Female; Aged; Buruli Ulcer; RNA, Ribosomal, 16S; Mycobacterium ulcerans; Mycobacterium Infections
PubMed: 36813163
DOI: 10.1016/j.jiac.2023.02.009 -
Frontiers in Genetics 2022Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex...
Cytokinesis is an essential process in bacterial cell division, and it involves more than 25 essential/non-essential cell division proteins that form a protein complex known as a divisome. Central to the divisome are the proteins FtsB and FtsL binding to FtsQ to form a complex FtsQBL, which helps link the early proteins with late proteins. The FtsQBL complex is highly conserved as a component across bacteria. Pathogens like , , , and are the causative agents of the bacterial Neglected Tropical Diseases Cholera, Buruli ulcer, Leprosy, and Trachoma, respectively, some of which seemingly lack known homologs for some of the FtsQBL complex proteins. In the absence of experimental characterization, either due to insufficient resources or the massive increase in novel sequences generated from genomics, functional annotation is traditionally inferred by sequence similarity to a known homolog. With the advent of accurate protein structure prediction methods, features both at the fold level and at the protein interaction level can be used to identify orthologs that cannot be unambiguously identified using sequence similarity methods. Using the FtsQBL complex proteins as a case study, we report potential remote homologs using Profile Hidden Markov models and structures predicted using AlphaFold. Predicted ortholog structures show conformational similarity with corresponding . proteins irrespective of their level of sequence similarity. Alphafold multimer was used to characterize remote homologs as FtsB or FtsL, when they were not sufficiently distinguishable at both the sequence or structure level, as their interactions with FtsQ and FtsW play a crucial role in their function. The structures were then analyzed to identify functionally critical regions of the proteins consistent with their homologs and delineate regions potentially useful for inhibitor discovery.
PubMed: 36685953
DOI: 10.3389/fgene.2022.1010870