Buruli Ulcers

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1		Gabriela Popa	--	1665	2023-08-30 20:58:07	\|
2	layout	Jessie Wu	Meta information modification	1665	2023-08-31 05:09:55	\|

This entry is adapted from the peer-reviewed paper 10.3390/pathogens12091088

Buruli ulcer (BU) is a bacterial skin infection that is caused by Mycobacterium ulcerans and mainly affects people who reside in the rural areas of Africa and in suburban and beach resort communities in Australia. The infection typically begins as a painless papule or nodule that gradually develops into a large ulcer that can cause substantial impairment, damaging soft tissues and even bones.

Buruli ulcer rifampin TB47

1. Introduction

Mycobacterium ulcerans (M. ulcerans) is a slow-growing mycobacterium and the causative agent of Buruli ulcer (BU), one of the most neglected tropical diseases ^[1]. The bacteria can be cultured in vitro at 32 °C using standard media for the mycobacterial culture. Whole-genome sequencing analyses revealed that M. ulcerans arose from ubiquitous fast-growing M. marinum, a nontuberculous bacteria that cause skin infections through the acquisition of a virulence plasmid (pMUM), which contains the genes responsible for the enzymes necessary for the production of macrolide toxins called mycolactones. The evolution of M. ulcerans involves reductive processes and the formation of pseudogenes, possibly to adapt to a more stable ecological niche, facilitated via the proliferation of specific insertion sequence (IS) elements in its genome, such as 213 copies of IS2404 and 91 copies of IS2606 ^[2]^[3].

2. New Therapeutic Strategies for Buruli Ulcer

In the last years, efforts have been made to develop new molecules for the treatment of BU (Table 1). It has been revealed that M. ulcerans is susceptible to Q203 (telacebec), a compound that acts on respiratory cytochrome bc1:aa3. This agent is a candidate for the treatment of tuberculosis; cytochrome bc1:aa3 has been shown to be the primary terminal oxidase in M. tuberculosis. Yet, M. tuberculosis exhibits an alternate bd-type terminal oxidase, which decreases the bactericidal and sterilizing effects of Q203 against this bacterium. Conversely, research on M. ulcerans strains recovered from BU patients in Africa and Australia revealed that, due to a mutation in the genes encoding the bd oxidase, these strains lacked an alternate terminal oxidase, rendering these predominant M. ulcerans strains highly vulnerable to Q203. This indicates that Q203 may be a helpful antibacterial drug in this scenario ^[4]. It has been shown that a single dose of Q203 effectively eliminates M. ulcerans in a mouse model of BU, with no recurrence observed for up to 19 weeks after treatment. These findings strongly suggest that Q203 holds promise for single-dose or other very short therapeutic approaches for BU. However, in cases of highly immunocompromised individuals, it may be necessary to consider higher doses, longer durations, or combining Q203 with other therapies ^[5]^[6].

Chauffour et al. have verified the efficacy of a new group of antibiotics against M. ulcerans using a BU mouse model. They proposed that tedizolid, selamectin, ivermectin, and benzothiazinone PBTZ169 had no bactericidal effect. In contrast, telacebec had a bactericidal effect. Therefore, they have proposed a treatment scheme with telacebec in combination with rifapentine or bedaquiline, two times a week for 8 weeks, which led to the sterilization of mouse footpads and prevented relapses over a period of 20 weeks ^[7]. Another recent study on a mouse model has shown that telacebec in combination with rifampin for a period of 2 weeks is associated with a relapse-free period of 24 weeks. Notably, the relapse rate was 25% in the group treated with rifampin and clarithromycin. Moreover, the authors evaluated the dose-ranging action of telacebec alone and in combination with rifampicin and discovered that rifampicin had no effect on telacebec activity ^[8]. A different promising molecule is TB47, which, in combination with oral antibiotics (rifampicin, clarithromycin, and clofazimine), can lead to the cure of BU in less than 2 weeks, provided that the treatment is administered daily and in 3 weeks if it is administered twice a week ^[9].

Fukano et al. assessed the effectiveness of a rifamycin derivative called rifalazil (RLZ) in treating advanced M. ulcerans infections using female BALB/c mice. The mice were initially infected with M. ulcerans and then administered RLZ orally at various doses. The untreated mice experienced a worsening of symptoms and reached the end-point within 5–8 weeks after infection. Conversely, the mice treated with RLZ demonstrated either an improvement or complete healing of footpad erythema, swelling, and erosion. Within 3 weeks of treatment, the bacterial counts in the treated mice significantly decreased compared to the untreated group. All treated mice survived without any signs of M. ulcerans infection. These results suggest that RLZ effectively treats advanced M. ulcerans infections in the mouse model ^[10]. Recently, Pidot et al. investigated the effect of SPR719, the active component of SPR720, a novel aminobenzimidazole, on M. ulcerans, M. marinum, and M. chimaera. SPR719 acts as an inhibitor of the ATPase activity of the DNA gyrase in mycobacteria. The study demonstrated that SPR719 inhibits the growth of the three non-tuberculous mycobacteria, with a minimum inhibitory concentration range of 0.125–4 μg/mL ^[11].

Table 1. Novel promising antimicrobial drugs for BU.

Antimicrobial Drug	Conclusion
Q203 (telacebec)	a compound that acts on respiratory cytochrome bc1:aa3a single dose of Q203 effectively eliminates M. ulcerans in a mouse model of BU, with no recurrence observed for up to 19 weeks after treatment ^[5]^[6]
TB47	its mechanism of action is unknownin combination with oral antibiotics (rifampicin, clarithromycin, and clofazimine), can lead to the cure of BU in less than 2 weeks provided that the treatment is administered daily and in 3 weeks if it is administered twice a week ^[9]
Rifalazil	blocks off the β-subunit in RNA polymeraseeffectively treats advanced M. ulcerans infections in the mouse model ^[10]
SPR719	acts as an inhibitor of the ATPase activity of the DNA gyrase in mycobacteriainhibits the growth of M. ulcerans ^[11]

In vitro studies have indicated that the activity of rifampicin and clarithromycin is increased by beta-lactams ^[12]. In light of this discovery, a group of researchers have recently proposed a multicenter randomized controlled trial in Benin to compare the standard treatment (rifampicin and clarithromycin, for 8 weeks) with the standard treatment in conjunction with amoxicillin/clavulanate, for 4 weeks. The study began in December 2021 and is to take place over a period of two years. The proposed treatment has the advantage that all antibiotics are administered orally and for a shorter period of time, which can significantly increase treatment adherence and may improve the healing process. Additionally, the required hospitalization days can be reduced, leading to lower costs ^[13]. A separate study confirms the synergistic action between beta-lactams and rifampicin or clarithromycin. The combination of amoxicillin and clavulanate has quick bactericidal activity and can efficiently eradicate extracellular bacteria, resulting in a decrease in the initial bacterial load and the local levels of the mycolactone toxin. This helps the recovery of the host’s immune response and the clearance of any remaining bacteria in the affected area ^[12].

Since no topical medication is currently available, a group of researchers looked into the plasma membrane fluidizer, diethyl azelate (DEA), as a possible topical drug. They have observed that DEA inhibits the immunosuppressive activity of M. ulcerans and slows down the appearance of ulcers and new lesions while promoting the healing process. M. ulcerans has an immunosuppressive effect that is mediated by mycolactone and appears to be inhibited by DEA ^[14]. In a recent article, poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles and gellan gum (GG) hydrogel were utilized to incorporate rifampicin and streptomycin for the cutaneous administration of antibiotics in BU. The obtained hydrogel exhibited a porous microstructure that has an extraordinary ability to retain water (superior to 2000%) and a controlled release of both antibiotics. These results can be the basis of future in vivo studies that will lead to the implementation of a topical treatment for BU and a decrease in adverse effects resulting from the systemic administration of antibiotics ^[15].

There is no effective vaccine for BU; however, numerous studies have been conducted in recent years with promising results. The initial investigations were carried out by Fenner in the 1950s ^[16]. The study by Pittet et al. is the first to explore how BCG immunization in humans affects the immune system’s response to M. ulcerans. The findings indicate that BCG vaccines generate an immune response to M. ulcerans that is similar in quality to the response seen in the case of M. tuberculosis. As BU cases may be increasing worldwide, even in countries where BCG immunization is not standard for children, BCG immunization could potentially serve as a valuable preventative measure ^[17]. However, it should be pointed out that vaccination in endemic areas for M. ulcerans have indicated only short-term protection, varying between 6 and 12 months. Looking back at previous studies, it is suggested that there is some level of protection against advanced forms of BU, but the results are not consistent. Various approaches have been employed in mouse studies, yet only a few vaccine candidates have shown better protection than BCG. Recombinant live whole-cell vaccines producing immunogenic antigens present encouraging evidence of protection, although achieving sterilizing immunity has not been proven yet. Additionally, targeting the mycolactone synthesis pathway has demonstrated effectiveness in mouse experiments and may be worth exploring in combination with BCG vaccination ^[18].

Foulon et al. draws attention to the fact that the diet could represent an adjuvant in the treatment of BU. Recent studies have shown that ketogenic diets help the tissue repair process, thus suggesting that such diets could prove useful for BU patients. They have observed that β-hydroxybutyrate, the main ketone body resulting from the ketogenic diet, inhibits the formation of mycolactone, one of the essential virulence factors in BU. Moreover, this diet promotes the host’s immune response ^[19]. Ugai et al. have analyzed the influence of nutritional status on the healing of BU. The study included a small number of patients (n = 11). The average follow-up period was 19 weeks, and they noticed that patients who have an adequate caloric intake have a faster healing process. It should be taken into account that the human body requires more calories to heal wounds. A total of 60% of patients with an adequate caloric intake achieved wound healing during the follow-up period, compared to only 17% in the case of the group with a low caloric intake. The authors suggest that the correct management of BU should also include educating patients on the principles of correct nutrition ^[20].

References

Wallace, J.R.; Mangas, K.M.; Porter, J.L.; Marcsisin, R.; Pidot, S.J.; Howden, B.; Omansen, T.F.; Zeng, W.; Axford, J.K.; Johnson, P.D.R.; et al. Mycobacterium Ulcerans Low Infectious Dose and Mechanical Transmission Support Insect Bites and Puncturing Injuries in the Spread of Buruli Ulcer. PLoS Negl. Trop. Dis. 2017, 11, e0005553.
Röltgen, K.; Pluschke, G.; Spencer, J.S.; Brennan, P.J.; Avanzi, C. The Immunology of Other Mycobacteria: M. ulcerans, M. leprae. Semin. Immunopathol. 2020, 42, 333–353.
Stinear, T.P.; Seemann, T.; Pidot, S.; Frigui, W.; Reysset, G.; Garnier, T.; Meurice, G.; Simon, D.; Bouchier, C.; Ma, L.; et al. Reductive Evolution and Niche Adaptation Inferred from the Genome of Mycobacterium ulcerans, the Causative Agent of Buruli Ulcer. Genome Res. 2007, 17, 192–200.
Scherr, N.; Bieri, R.; Thomas, S.S.; Chauffour, A.; Kalia, N.P.; Schneide, P.; Ruf, M.-T.; Lamelas, A.; Manimekalai, M.S.S.; Grüber, G.; et al. Targeting the Mycobacterium ulcerans Cytochrome Bc1:Aa3 for the Treatment of Buruli Ulcer. Nat. Commun. 2018, 9, 5370.
Komm, O.; Almeida, D.V.; Converse, P.J.; Omansen, T.F.; Nuermberger, E.L. Impact of Dose, Duration, and Immune Status on Efficacy of Ultrashort Telacebec Regimens in Mouse Models of Buruli Ulcer. Antimicrob. Agents Chemother. 2021, 65, e0141821.
Thomas, S.S.; Kalia, N.P.; Ruf, M.-T.; Pluschke, G.; Pethe, K. Toward a Single-Dose Cure for Buruli Ulcer. Antimicrob. Agents Chemother. 2020, 64, e00727-20.
Chauffour, A.; Robert, J.; Veziris, N.; Aubry, A.; Pethe, K.; Jarlier, V. Telacebec (Q203)-Containing Intermittent Oral Regimens Sterilized Mice Infected with Mycobacterium ulcerans after Only 16 Doses. PLoS Negl. Trop. Dis. 2020, 14, e0007857.
Almeida, D.V.; Converse, P.J.; Omansen, T.F.; Tyagi, S.; Tasneen, R.; Kim, J.; Nuermberger, E.L. Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model. Antimicrob. Agents Chemother. 2020, 64, e00259-20.
Gao, Y.; Hameed, H.M.A.; Liu, Y.; Guo, L.; Fang, C.; Tian, X.; Liu, Z.; Wang, S.; Lu, Z.; Islam, M.M.; et al. Ultra-Short-Course and Intermittent TB47-Containing Oral Regimens Produce Stable Cure against Buruli Ulcer in a Murine Model and Prevent the Emergence of Resistance for Mycobacterium ulcerans. Acta Pharm. Sin. B 2021, 11, 738–749.
Fukano, H.; Nakanaga, K.; Goto, M.; Yoshida, M.; Ishii, N.; Hoshino, Y. Therapeutic Efficacy of Rifalazil (KRM-1648) in a M. ulcerans-Induced Buruli Ulcer Mouse Model. PLoS ONE 2022, 17, e0274742.
Pidot, S.J.; Porter, J.L.; Lister, T.; Stinear, T.P. In Vitro Activity of SPR719 against Mycobacterium ulcerans, Mycobacterium Marinum and Mycobacterium Chimaera. PLoS Negl. Trop. Dis. 2021, 15, e0009636.
Arenaz-Callao, M.P.; González del Río, R.; Lucía Quintana, A.; Thompson, C.J.; Mendoza-Losana, A.; Ramón-García, S. Triple Oral Beta-Lactam Containing Therapy for Buruli Ulcer Treatment Shortening. PLoS Negl. Trop. Dis. 2019, 13, e0007126.
Johnson, R.C.; Sáez-López, E.; Anagonou, E.S.; Kpoton, G.G.; Ayelo, A.G.; Gnimavo, R.S.; Mignanwande, F.Z.; Houezo, J.-G.; Sopoh, G.E.; Addo, J.; et al. Comparison of 8 Weeks Standard Treatment (Rifampicin plus Clarithromycin) vs. 4 Weeks Standard plus Amoxicillin/Clavulanate Treatment to Shorten Buruli Ulcer Disease Therapy (the BLMs4BU Trial): Study Protocol for a Randomized Controlled Multi-Centre Trial in Benin. Trials 2022, 23, 559.
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Fenner, F. Homologous and Heterologous Immunity in Infections of Mice with Mycobacterium ulcerans and Mycobacterium Balnei. Am. Rev. Tuberc. 1957, 76, 76–89.
Pittet, L.F.; Tebruegge, M.; Dutta, B.; Donath, S.; Messina, N.; Casalaz, D.; Hanekom, W.A.; Britton, W.J.; Robins-Browne, R.; Curtis, N.; et al. Mycobacterium ulcerans-Specific Immune Response after Immunisation with Bacillus Calmette-Guérin (BCG) Vaccine. Vaccine 2021, 39, 652–657.
Muhi, S.; Stinear, T.P. Systematic Review of M. Bovis BCG and Other Candidate Vaccines for Buruli Ulcer Prophylaxis. Vaccine 2021, 39, 7238–7252.
Foulon, M.; Robbe-Saule, M.; Esnault, L.; Malloci, M.; Mery, A.; Saint-André, J.-P.; Croue, A.; Kempf, M.; Homedan, C.; Marion, E. Ketogenic Diet Impairment of Mycobacterium ulcerans Growth and Toxin Production and Enhancement of Host Response to Infection in an Experimental Mouse Model. J. Infect. Dis. 2021, 224, 1973–1983.
Ugai, K.; Koffi, D.Y.; Kouadio, K.; Yao, A.; Yotsu, R.R. Nutritional Status and Wound Healing in Patients with Mycobacterium ulcerans Disease (Buruli Ulcer): A Pilot Study from Rural Côte d’Ivoire. Eur. J. Dermatol. 2022, 32, 227–236.

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Gabriela Loredana Popa

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Mircea Ioan Popa

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Update Date: 31 Aug 2023

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1. Introduction

2. New Therapeutic Strategies for Buruli Ulcer

References