Buruli Research Articles

Tuberculosis management and referral practices among traditional medicine practitioners in Lagos, Nigeria

Introduction: Despite the potential role of Traditional Birth Attendants (TBAs) and Traditional Healers (THs), little is known about their knowledge of tuberculosis (TB) management and referral practices in Nigeria. Objective: To determine knowledge and self-reported practices of traditional birth attendants and traditional healers in managing TB in Lagos, Nigeria. Methods: A cross-sectional study of 120 THs and TBAs in three high TB burden Local Government Areas (LGAs) in Lagos, Nigeria. Data were collected between April 2018 to September 2018 through interviewer-administered questionnaires. We used Statistical Package for Social Sciences software for data analyses. Independent predictors of being TBA or TH were determined using logistic regression at the statistical significance of P0.05 and 95% confidence interval. Results: TB knowledge increased from 52.7% pre-test to 61.7% post-test and did not differ between TBAs and THs. Of the 120 Traditional Medical Practitioners studied, 70% (84) never treated TB; 57.3 % (69) ever referred chronic cough patients to a health facility; 90% (108) were willing to collaborate with National Tuberculosis, Leprosy and Buruli Ulcer Control Programme (NTBLCP), 85% (102) attached monetary and token incentive as a condition for the collaboration. THs had decreased odds of ever referring TB patient to the hospital (AOR: 0.3, 95% CI:0.14-0.64, P=0.002); currently referring TB patients (AOR: 0.06, 95% CI:0.02-0.17, P0.0001) and consulting 40 patients in a year (AOR: 0.22,95% CI:0.09-0.53, P0.0001). Conclusion: Majority of the THs and TBAs were willing to collaborate with NTBLCP in the identification and referral of Presumptive TB patients. We suggest that NTBLCP empowers the TBAs and THs to help with an early referral of TB patients.

Buruli-RifDACC: Evaluation of the efficacy and cost-effectiveness of high-dose versus standard-dose rifampicin on outcomes in Mycobacteriumulcerans disease, a protocol for a randomised controlled trial in Ghana.

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. 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. 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. Pan African Clinical Trials Repository (registration number; PACTR202011867644311). Registered on 30 th November 2020.

Undermining Ulcers in Juvenile Dermatomyositis.

A 6-year-old boy with a history of refractory anti–transcription intermediary factor 1-γ (anti–TIF1-γ) juvenile dermatomyositis presented to the rheumatology clinic with skin ulcers of 10 days in duration. Physical examination revealed normal muscle for strength. Heliotrope rash, Gottron sign, and diffuse erythematous eruption on the neck, trunk, and buttocks were observed (Figs. 1A, B). No calcinosis cutis, and 2 ulcers (4 × 3 cm, 1 × 1 cm) on the left upper arm deep into the underlying biceps with well-circumscribed margins were observed (Fig. 2). Laboratory studies including muscle enzymes were unremarkable. Patients with anti–TIF1-γ juvenile dermatomyositis tend to have chronic or treatment-resistant disease course. Undermining ulcer is a severe cutaneous manifestation associated with vasculitis or vascular damage due to panniculitis or calcinosis. After 2 cycles of monthly intravenous immunoglobulin therapy (~1.7 g/kg/month) along with continuing use of prednisone and thalidomide at previous dose, the ulcers healed completely (Fig. 3), and other skin lesions improved significantly as well.FIGURE 1: Gottron sign (A) and diffuse erythematous eruption on the buttocks (B).FIGURE 2: Undermining ulcers on the left upper arm.FIGURE 3: The ulcers healed completely after 2 months of treatment.Differential diagnosis: Pyoderma gangrenosum Pressure ulcer Buruli ulcer Dermatomyositis (anti–TIF1-γ, anti-MDA5)

Gold Panning-Related Chronic Cutaneous Ulcers in Guinea, West Africa.

Chronic cutaneous ulcers caused potentially by several pathogens are of increasing concern in endemic tropical countries, including Guinea in West Africa, in rural populations exposed to aquatic environments during recreational, domestic, or agricultural activities. By plotting 1,011 cases of chronic cutaneous ulcers classified under the name Buruli ulcer in 24 of 33 Guinea health districts (72%) between 2018 and 2020 against the gold map and gold-panning map of Guinea, we revealed a significant spatial association between chronic cutaneous ulcer foci and gold-panning foci (P < 0.05), but not with nongold-panning foci (P = 0.12) in Guinea. Gold panning should be listed as an additional economic activity exposing populations to chronic cutaneous ulcers. Further research may aim to clarify whether any geological and biologic factors underlie such an association, besides the possibility that the unprotected skin of gold panners may be exposed to opportunistic, pathogen-contaminated environments in gold-panning areas.

Mapping the FtsQBL divisome components in bacterial NTD pathogens as potential drug targets.

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 Vibrio cholerae, Mycobacterium ulcerans, Mycobacterium leprae, and Chlamydia trachomatis 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 E. coli 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.

Towards the development of reliable and economical mHealth solutions: A methodology for accurate detection of Buruli ulcer for hard-to-reach communities

mHealth interventions have the potential to increase access to healthcare for the most hard-to-reach communities. For rural communities suffering disproportionately from skin-related NTDs, and Buruli ulcer, there is a need for low-cost, non-invasive and mobile tools for the early detection and management of disease. Dermoscopy is a noninvasive in-vivo technique that has been useful in improving the diagnostic accuracy of pigmented skin lesions based on anatomical features and morphological structures of lesions.ObjectivesUsing dermoscopy, this study develops the automated tools necessary for developing an effective mHealth intervention towards identifying BU lesions in the early stages. Methods: This imaging methodology relies on an external attachment, a dermoscope, which uses polarized light to cancel out skin surface reflections. In our initial studies we used a dermoscope with only crosspolarized white-light (DL100, 3Gen) but later we adopted a more advanced multispectral dermoscope (DLIIm, 3Gen). The latter employed additional monochromatic light at different wavelengths of the visible spectral range, specifically blue (470 nm), yellow (580 nm), and red (660 nm) color, to visualize pigmented structures of skin layers at different depths.ResultsResults obtained using a subset of 58 white-light images with confirmed diagnosis (16 lesions BU and 42 lesions non-BU) resulting in sensitivity of 100 and specificity of 88.10, with an overall accuracy of 94.05 at 95% CI. Performance obtained using a second dataset of 197 dermoscopic multispectral images (16 lesions BU and 181 lesions non-BU) resulted in sensitivity of 90.00% and specificity of 93.39% with a balanced accuracy of 91.69% (86.95% to 95.12% at 95% CI).ConclusionsThis system will continue to perform even as the technology evolves and newer dermoscopes are available. Subsequent studies involve the DL4 which provides more uniform and brighter illumination, higher lesion magnification, and wider field of view which, combined with the superb resolution of modern smartphones, can result in faster and more accurate lesion assessment. This is an important step for the development of mHealth tools for use by non-specialists in community settings for the early detection of Buruli ulcer, skin-NTDs, and other dermatologic conditions associated with disease, including wound healing and management of disease progression.

Challenges in the management of Buruli ulcer in Nigeria – A case report and literature review

Buruli ulcer (BU) is a disfiguring infective skin lesion caused by Mycobacteriumulcerans. If untreated, BU may lead to extensive soft-tissue loss and other complications. The objective of this study is to highlight the challenges encountered in the diagnosis and management of a patient with BU in our hospital. The patient is a 5-year-old boy who presented with an extensive nonhealing ulcer, knee deformity, and fever. He was initially managed as a case of nonspecific ulcer. A recurrence of the ulcer with loss of part of the skin grafts a week after discharge led to the clinical suspicion of BU which was confirmed using microscopy. In South Western Nigeria, the major constraint in the management of BU includes underdiagnosing of the disease because it is not often screened for due to absence or insufficient standard diagnostic instruments dedicated for that purpose.

Assessment of the 2 Conventional Physiotherapy Sessions Alone versus One Session Associated to Kabat’s Method in the Rehabilitation of Buruli Ulcer Patients (PUB), with Functional Limitations in the District Hospital of Akonolinga, Cameroon

Assessment of the 2 Conventional Physiotherapy Sessions Alone versus One Session Associated to Kabat’s Method in the Rehabilitation of Buruli Ulcer Patients (PUB), with Functional Limitations in the District Hospital of Akonolinga, Cameroon

Prevalence of skin Neglected Tropical Diseases and superficial fungal infections in two peri-urban schools and one rural community setting in Togo.

Skin neglected tropical diseases (NTDs), are endemic and under-diagnosed in many lower-income communities. The objective of this study was to determine the prevalence of skin NTDs and fungal infections in two primary schools and a community setting in rural Togo. This was a cross-sectional study that took place between June-October 2021. The two primary schools are located on the outskirts of Lomé, the capital city. The community setting was Ndjéi, in north-east Togo. Study sites were purposively selected. Dermatologists examined the skin of study participants. Diagnosis of skin NTDs were made clinically. A total of 1401 individuals were examined, 954 (68.1%) from Ndjéi community, and 447 (31.9%) were children in the schools. Cutaneous skin infections were diagnosed in 438 (31.3%) participants, of whom 355 (81%) were in community settings. There were 105 observed skin NTDs (7.5%). Within the school setting, there were 20 individuals with NTDs (4.5% of 447 participants), and 85 NTDs (8.9%) from 954 community participants. Across all settings 68/1020 (6.7%) NTDs were in children, and 37/381 (9.7%) in adults. In addition, there were 333 observed mycoses (23.8% prevalence). The main cutaneous NTDs diagnosed were scabies (n = 86; 6.1%) and suspected yaws (n = 16, 1.1%). The prevalence of scabies in schools was 4.3%, and 7.0% in the rural community. One case of leprosy was diagnosed in each school and the rural community, and one suspected Buruli Ulcer case in the community. In the school setting, five (6%) children with a skin NTD reported being stigmatised, four of whom had refused to attend school because of their dermatosis. In Ndjéi, 44 (4.6%) individuals reported having experienced stigma and 41 (93.2%) of them missed at least one day of school or work. This study shows that the burden of scabies and skin infections such as superficial mycoses is high in the school and rural community settings in Togo, with associated presence of stigma. Improved health promotion and education across institutional and community settings may reduce stigma and encourage early reporting of skin infection cases to a health facility.

Perceived water-related risk factors of Buruli ulcer in two villages of south-central Côte d'Ivoire.

Buruli ulcer, caused by Mycobacterium ulcerans, is a neglected tropical skin disease that is primarily endemic in West and Central Africa, including Côte d'Ivoire. Studies indicate that M. ulcerans infections are caused by contact with an environmental reservoir of the bacteria, governed by specific human biological conditions. Yet, the nature of this reservoir and the exact mode of transmission remain unknown. To identify ecologic risk factors of Buruli ulcer in south-central Côte d'Ivoire, we pursued a qualitative study matched with geo-referencing inquiry. Embedded in a broader integrated wound management research project, we (i) mapped households and water sources of laboratory confirmed Buruli ulcer cases and (ii) interviewed 12 patients and four health care workers to assess exposure to surface water and to deepen the understanding of perceived transmission pathways. Water availability, accessibility, and affordability were reported as key determinants for choosing water resources. Furthermore, perceived risks were related to environmental, structural, and individual factors. Despite the presence of improved water sources (e.g., drilled wells), communities heavily relied on unprotected surface water for a multitude of activities. The nearby Bandama River and seasonal waterbodies were frequently used for washing, bathing, and collection of water for drinking and cooking. Many residents also reported to cross the river on a daily basis for agricultural chores, and hence, are exposed to stagnant water during farming activities. Our study in two Buruli ulcer endemic villages in south-central Côte d'Ivoire revealed a wide range of water-related domestic activities that might expose people to an increased risk of contracting the disease. Environmental, biological, social, and cultural risk factors are closely interlinked and should be considered in future investigations of Buruli ulcer transmission. Active participation of the communities is key to better understand their circumstances to advance research and fight against Buruli ulcer and other neglected tropical diseases.

November Meeting Report "Mycobacterium ulcerans (Buruli ulcer) in our native mammals in the wild" Dr. Christina McCowan (Uni Melbourne)

November Meeting Report "Mycobacterium ulcerans (Buruli ulcer) in our native mammals in the wild" Dr. Christina McCowan (Uni Melbourne)

Buruli-RifDACC: Evaluation of the efficacy and cost-effectiveness of high-dose versus standard-dose rifampicin on outcomes in Mycobacterium ulcerans disease, a protocol for a randomised controlled trial in Ghana [version 1; peer review: 2 approved

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. 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. 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.

Identification of potential candidate vaccines against Mycobacterium ulcerans based on the major facilitator superfamily transporter protein.

Buruli ulcer is a neglected tropical disease that is characterized by non-fatal lesion development. The causative agent is Mycobacterium ulcerans (M. ulcerans). There are no known vectors or transmission methods, preventing the development of control methods. There are effective diagnostic techniques and treatment routines; however, several socioeconomic factors may limit patients' abilities to receive these treatments. The Bacillus Calmette-Guérin vaccine developed against tuberculosis has shown limited efficacy, and no conventionally designed vaccines have passed clinical trials. This study aimed to generate a multi-epitope vaccine against M. ulcerans from the major facilitator superfamily transporter protein using an immunoinformatics approach. Twelve M. ulcerans genome assemblies were analyzed, resulting in the identification of 11 CD8+ and 7 CD4+ T-cell epitopes and 2 B-cell epitopes. These conserved epitopes were computationally predicted to be antigenic, immunogenic, non-allergenic, and non-toxic. The CD4+ T-cell epitopes were capable of inducing interferon-gamma and interleukin-4. They successfully bound to their respective human leukocyte antigens alleles in in silico docking studies. The expected global population coverage of the T-cell epitopes and their restricted human leukocyte antigens alleles was 99.90%. The population coverage of endemic regions ranged from 99.99% (Papua New Guinea) to 21.81% (Liberia). Two vaccine constructs were generated using the Toll-like receptors 2 and 4 agonists, LprG and RpfE, respectively. Both constructs were antigenic, non-allergenic, non-toxic, thermostable, basic, and hydrophilic. The DNA sequences of the vaccine constructs underwent optimization and were successfully in-silico cloned with the pET-28a(+) plasmid. The vaccine constructs were successfully docked to their respective toll-like receptors. Molecular dynamics simulations were carried out to analyze the binding interactions within the complex. The generated binding energies indicate the stability of both complexes. The constructs generated in this study display severable favorable properties, with construct one displaying a greater range of favorable properties. However, further analysis and laboratory validation are required.

A combined effort of 11 laboratories in the WHO African region to improve quality of Buruli ulcer PCR diagnosis: The "BU-LABNET".

Buruli ulcer is one of the 20 neglected tropical diseases in the world. This necrotizing hypodermitis is a chronic debilitating disease caused by an environmental Mycobacterium ulcerans. At least 33 countries with tropical, subtropical and temperate climates have reported Buruli ulcer in African countries, South America and Western Pacific regions. Majority of cases are spread across West and Central Africa. The mode of transmission is unclear, hindering the implementation of adequate prevention for the population. Currently, early diagnosis and treatment are crucial to minimizing morbidity, costs and preventing long-term disability. Biological confirmation of clinical diagnosis of Buruli ulcer is essential before starting chemotherapy. Indeed, differential diagnosis are numerous and Buruli ulcer has varying clinical presentations. Up to now, the gold standard biological confirmation is the quantitative PCR, targeting the insertion sequence IS2404 of M. ulcerans performed on cutaneous samples. Due to the low PCR confirmation rate in endemic African countries (under 30% in 2018) for numerous identified reasons within this article, 11 laboratories decided to combine their efforts to create the network "BU-LABNET" in 2019. The first step of the network was to harmonize the procedures and ship specific reagents to each laboratory. With this system in place, implementation of these procedures for testing and follow-up was easy and the laboratories were able to carry out their first quality control with a very high success rate. It is now time to integrate other neglected tropical diseases to this platform, such as yaws or leprosy.

Buruli Ulcer and Medical Geo-Microbiology.

Buruli ulcer is a chronic debilitating infectious disease caused by the pathogen Mycobacterium ulcerans, which can be cured if diagnosed and treated in an early stage. However, advanced cases need antibiotic treatment followed by surgical interventions. In this context, an extremely effective and less expensive treatment modality can be developed by means of an extended topical application of certain selected natural clay minerals, most of the time containing illite-smectite having some iron content. There is a scope for developing the speciality, medical geo-microbiology, which is truly a multidisciplinary one, for finding a cure for the severe and advanced cases of BU.

Utilising community volunteers can increase the detection and referral of Buruli ulcer cases in endemic communities in Southeast, Nigeria

BackgroundBuruli ulcer (BU) is a debilitating neglected tropical disease which causes disability and mostly affects inhabitants in impoverished settings where access to medical care is challenging. This study aims to determine the effect of training community members as volunteers for or in the detection and referral of people who have Buruli ulcer to the hospital.MethodsThe following study is a before and after study in the BU-endemic Local Government Areas (LGA) of Ebonyi State. A cluster random sampling technique was used to select 90 volunteers from three LGAs (30 from each LGA). In each LGA, the volunteers underwent a one-day training and six months field work to identify all those who have any form of ulcer on any part of their bodies. A short questionnaire was used to capture socio-demographic characteristics of the patient, site of the ulcer, duration of the ulcer, initial appearance of the ulcer, referral to hospital, result of laboratory investigation, and treatment received. The data was analysed using the Statistical Package for Social Sciences (SPSS) for Microsoft Windows version 20 software. The Z test statistic was used to compare the number of referred BU patients before and after the intervention by LGA. The Chi square test was used to examine the association between the dependent and independent variables.ResultsThe mean age of volunteers was 39 ± 9.5 while mean age of the patients was 42.3 ± 17.1. Most of the ulcers were on the legs (79.4%) and lasted 1–5 years (65.6%). There was a significant increase in the proportion of BU suspects identified by the community volunteers in all 3 LGAs (Afikpo north (p = < 0.001), Abakaliki (p = 0.02), Ikwo (p = 0.001). The duration of the ulcer was associated with the detection and referral of the patients with higher levels of detection and referral among those whose ulcer had lasted 1–5 years in two of the LGAs (P < 0.001).ConclusionWe recommend that program managers and stakeholders integrate and scale up the services of trained community health volunteers for the rapid detection of Buruli ulcer cases in rural endemic communities. Awareness and sensitization campaigns on BU preventive measures should be intensified.

Mycobacterium ulcerans.

Mycobacterium ulcerans is the etiological agent of Buruli ulcer, an emerging neglected tropical disease. This necrotizing hypodermatitis affects mostly children in West and Central Africa. Mycolactone, the main virulence factor of M. ulcerans, is a macrolide toxin with pleiotropic effects that allow the establishment of M. ulcerans in its hosts. Although early infection can be treated with antibiotics, late stages also require surgery, skin grafts, and functional rehabilitation to limit irreversible damage.

BuDb: A Curated Drug Discovery Database for Buruli Ulcer

Buruli ulcer (BU), a severe skin disease is caused by Mycobacterium ulcerans. There are concerns of therapeutic inefficacy of existing drugs coupled with chemoresistance. Databases have been shown to augment data mining and integrative systems pharmacology approaches towards the search for novel therapeutic moieties. So far, there is no known integrated database solely dedicated to BU drug discovery. In this work, Buruli ulcer database (BuDb) is a “one-stop-shop” knowledgebase for supporting BU drug discovery. It contains both manually verified literature and database-curated data on BU. The BuDb provides comprehensive information on the various drug targets, tested compounds, existing drugs, ethnopharmacological plants and information on the genome of M. ulcerans. It also contains cross-referenced links to databases including PubMed, PubChem, DrugBank, NCBI, Gene Ontology (GO), UniProt, Prota4u, String database, KEGG Pathway and KEGG genome database. The BuDb has been implemented with accessibility features such as keyword and specific searches as well as browsing. BuDb is the first useful online repository of its kind integrated with enriched datasets that can aid in the discovery of new biotherapeutic entities for BU. BuDb can be freely accessed at http://197.255.126.13:3000/ .

Modified aluminosilicates display antibacterial activity against nontuberculous mycobacteria and adsorb mycolactone and Mycobacterium ulcerans in vitro

Mycobacterium ulcerans (MU) infection of skin and soft tissue leads to chronic skin ulceration known as Buruli ulcer. MU releases a lipid-like toxin, mycolactone, that diffuses into the tissue, effecting disease through localized tissue necrosis and immunosuppression. Cutaneous Buruli ulcer wounds slowly advance from a painless pre-ulcerative stage to an ulcerative lesion, leading to disparities in the timing of medical intervention and treatment outcomes. Novel Buruli ulcer wound management solutions could complement and supplement systemically administered antimicrobials and reduce time to healing. Capitalizing on nanopore structure, adsorption, and exchange capacities, aluminosilicate nanozeolites (nZeos) and geopolymers (GPs) were developed and investigated in the context of therapeutics for mycobacterial disease ulcerative wound care. nZeos were ion exchanged with copper or silver to assess the antimicrobial activity against MU and Mycobacterium marinum, a rapid growing, genetic ancestor of MU that also causes skin and soft tissue infections. Silver- and copper-exchanged nZeos were bactericidal against MU, while only silver-exchanged nZeos killed M. marinum. To mediate adsorption at a biological scale, GPs with different pore sizes and altered surface modifications were generated and assessed for the ability to adsorb MU and mycolactone. Macroporous GPs with and without stearic acid modification equivalently adsorbed MU cells, while mesoporous GPs with stearic acid adsorbed mycolactone toxin significantly better than mesoporous GPs or GPs modified with phenyltriethoxysilane (PTES). In cytotoxicity assays, Cu-nZeos lacked toxicity against Detroit 551, U-937, and WM-115 cells. GPs demonstrated limited cytotoxicity in Detroit 551 and WM-115, but produced time-dependent toxicity in U-937 cells. With their large surface area and adsorptive capacities, aluminosilicates nZeos and GPs may be modified and developed to support conventional BU wound care. Topical application of nZeos and GPs could kill MU within the cutaneous wound environment and physically remove MU and mycolactone with wound dressing changes, thereby improving wound healing and overall patient outcomes.

Can membrane composition traffic toxins? Mycolactone and preferential membrane interactions

Mycolactone is a cytotoxic and immunosuppressive macrolide produced by Mycobacterium ulcerans and the sole causative agent of the neglected tropical skin disease Buruli ulcer. The toxin acts by invading host cells and interacting with intracellular targets to disrupt multiple fundamental cellular processes. Mycolactone’s amphiphilic nature enables strong interactions with lipophilic environments, including cellular membranes; however, the specificity of these interactions and the role of membranes in the toxin’s pathogenicity remain unknown. It is likely that preferential interactions with lipophilic carriers play a key role in the toxin’s distribution in the host, which, if understood, could provide insights to aid in the development of needed diagnostics for Buruli ulcer disease. In this work, molecular dynamics simulations were combined with enhanced free-energy sampling to characterize mycolactone’s association with and permeation through models of the mammalian endoplasmic reticulum (ER) and plasma membranes (PMs). We find that increased order in the PMs not only leads to a different permeation mechanism compared with that in the ER membrane but also an energetic driving force for ER localization. Increased hydration, membrane deformation, and preferential interactions with unsaturated lipid tails stabilize the toxin in the ER membrane, while disruption of lipid packing is a destabilizing force in the PMs.