REPURPOSING CLINICALLY APPROVED ANTIBACTERIAL DRUGS FOR
Treponematoses Therapy
Trep-AB is a five-year research project funded by a European Research Council (ERC) Starting Grant. Implemented in collaboration with the University of Washington (UW), the project aims at identifying effective, alternative therapeutic options for the two most common human treponematoses: syphilis and yaws.
The Trep-AB project will achieve this by repurposing (i.e., finding new applications for) approved antibacterial drugs, to provide a smart, affordable, and effective solution to the lack of antibiotics for these conditions. The discovery of new effective antibiotics has the potential to change treatment policies worldwide.
Selected publications
Ávila-Nieto, Carlos; Pedreño-Lopez, Núria; Mitjà, Oriol; et al.
Syphilis vaccine: challenges, controversies and opportunities Journal Article
In: Frontiers in Immunology, vol. 14, 2023.
@article{NIETO2023SUBCUT,
title = {Syphilis vaccine: challenges, controversies and opportunities},
author = {Carlos Ávila-Nieto and Núria Pedreño-Lopez and Oriol Mitjà and Bonaventura Clotet and Julà Blanco and Jorge Carrillo},
doi = {https://doi.org/10.3389/fimmu.2023.1126170},
year = {2023},
date = {2023-01-01},
journal = {Frontiers in Immunology},
volume = {14},
abstract = {Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.
Mitjà, Oriol; Suñer, Clara; Giacani, Lorenzo; et al.
Treatment of bacterial sexually transmitted infections in Europe: gonorrhoea, Mycoplasma genitalium, and syphilis Journal Article
In: The Lancet Regional Health – Europe, vol. 34, pp. 100737, 2023, ISSN: 2666-7762.
@article{MITJA2023100737,
title = {Treatment of bacterial sexually transmitted infections in Europe: gonorrhoea, Mycoplasma genitalium, and syphilis},
author = {Oriol Mitjà and Clara Suñer and Lorenzo Giacani and Martí Vall-Mayans and George-Sorin Tiplica and Jonathan D. C. Ross and Catriona S. Bradshaw},
doi = {https://doi.org/10.1016/j.lanepe.2023.100737},
issn = {2666-7762},
year = {2023},
date = {2023-01-01},
journal = {The Lancet Regional Health - Europe},
volume = {34},
pages = {100737},
abstract = {This review explores the therapeutic challenges of sexually transmitted infections (STI) in Europe, which include increasing antimicrobial resistance and limited progress in drug discovery. We primarily focus on gonorrhoea, Mycoplasma genitalium, and syphilis infections. For gonorrhoea with escalating resistance rates we explore the possibility of combining ceftriaxone with another antibiotic or using alternative antibiotics to mitigate resistance emergence, and we provide insights on the ongoing evaluation of new antimicrobials, like gepotidacin and zoliflodacin. In the case of M. genitalium, which exhibits high resistance rates to first and second-line treatments, we emphasize the importance of resistance-guided therapy in regions with elevated resistance levels, and highlight the limited alternative options, such as pristinamycin and minocycline. Furthermore, we address the challenges posed by syphilis, where the primary treatment consists of penicillin or doxycycline, with challenges arising in neurosyphilis, allergy, pregnancy, and supply shortages and discuss the ongoing evaluation of alternative antimicrobials (e.g., ceftriaxone, cefixime, linezolid). Our findings identify priority actions and provide concrete solutions for long-term effective management of STIs and antimicrobial resistance mitigation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This review explores the therapeutic challenges of sexually transmitted infections (STI) in Europe, which include increasing antimicrobial resistance and limited progress in drug discovery. We primarily focus on gonorrhoea, Mycoplasma genitalium, and syphilis infections. For gonorrhoea with escalating resistance rates we explore the possibility of combining ceftriaxone with another antibiotic or using alternative antibiotics to mitigate resistance emergence, and we provide insights on the ongoing evaluation of new antimicrobials, like gepotidacin and zoliflodacin. In the case of M. genitalium, which exhibits high resistance rates to first and second-line treatments, we emphasize the importance of resistance-guided therapy in regions with elevated resistance levels, and highlight the limited alternative options, such as pristinamycin and minocycline. Furthermore, we address the challenges posed by syphilis, where the primary treatment consists of penicillin or doxycycline, with challenges arising in neurosyphilis, allergy, pregnancy, and supply shortages and discuss the ongoing evaluation of alternative antimicrobials (e.g., ceftriaxone, cefixime, linezolid). Our findings identify priority actions and provide concrete solutions for long-term effective management of STIs and antimicrobial resistance mitigation.
Gökengin, Deniz; Noori, Teymur; Alemany, Andrea; et al.
Prevention strategies for sexually transmitted infections, HIV, and viral hepatitis in Europe Journal Article
In: The Lancet Regional Health – Europe, vol. 34, pp. 100738, 2023, ISSN: 2666-7762.
@article{GOKENGIN2023100738,
title = {Prevention strategies for sexually transmitted infections, HIV, and viral hepatitis in Europe},
author = {Deniz Gökengin and Teymur Noori and Andrea Alemany and Carlo Bienkowski and Geoffroy Liegon and Ahmet Çağkan İnkaya and Jorge Carrillo and Georg Stary and Katja Knapp and Oriol Mitja and Jean-Michel Molina},
doi = {https://doi.org/10.1016/j.lanepe.2023.100738},
issn = {2666-7762},
year = {2023},
date = {2023-01-01},
journal = {The Lancet Regional Health - Europe},
volume = {34},
pages = {100738},
abstract = {The current prevention efforts for STIs, HIV and viral hepatitis in the WHO European Region, especially in the Central and Eastern subregions, are hindered by healthcare disparities, data gaps, and limited resources. In this comprehensive narrative review, we aim to highlight both achievements and persisting challenges while also exploring new developments that could significantly impact the prevention of these infections in the near future. While pre-exposure prophylaxis (PrEP) for HIV has been broadly approved and implemented in 38 out of 53 countries in the region, challenges remain, including cost, limited licensing, and incomplete adherence. We explore innovative approaches like on-demand PrEP, long-acting injectable cabotegravir, and intravaginal rings that have shown promising results, alongside the use of six-monthly lenacapavir, the outcomes of which are pending. Additionally, the potential of doxycycline post-exposure prophylaxis has been discussed, revealing efficacy in reducing chlamydia and syphilis risk, but effectiveness against gonorrhoea being contingent on tetracycline resistance rates, and the need of further data to determine potential resistance development in other bacteria and its impact on the gut microbiome. We examine successful vaccination campaigns against HBV and HPV, the ongoing development of vaccines for chlamydia, syphilis, herpesvirus, and gonorrhoea, and challenges in HIV vaccine research, including lines of research with significant potential like sequential immunization, T-cell responses, and mRNA technology. This review underscores the research endeavors that pave the way for a more resilient and robust approach to combating STIs, HIV, and viral hepatitis in the region.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The current prevention efforts for STIs, HIV and viral hepatitis in the WHO European Region, especially in the Central and Eastern subregions, are hindered by healthcare disparities, data gaps, and limited resources. In this comprehensive narrative review, we aim to highlight both achievements and persisting challenges while also exploring new developments that could significantly impact the prevention of these infections in the near future. While pre-exposure prophylaxis (PrEP) for HIV has been broadly approved and implemented in 38 out of 53 countries in the region, challenges remain, including cost, limited licensing, and incomplete adherence. We explore innovative approaches like on-demand PrEP, long-acting injectable cabotegravir, and intravaginal rings that have shown promising results, alongside the use of six-monthly lenacapavir, the outcomes of which are pending. Additionally, the potential of doxycycline post-exposure prophylaxis has been discussed, revealing efficacy in reducing chlamydia and syphilis risk, but effectiveness against gonorrhoea being contingent on tetracycline resistance rates, and the need of further data to determine potential resistance development in other bacteria and its impact on the gut microbiome. We examine successful vaccination campaigns against HBV and HPV, the ongoing development of vaccines for chlamydia, syphilis, herpesvirus, and gonorrhoea, and challenges in HIV vaccine research, including lines of research with significant potential like sequential immunization, T-cell responses, and mRNA technology. This review underscores the research endeavors that pave the way for a more resilient and robust approach to combating STIs, HIV, and viral hepatitis in the region.
Mitjà, Oriol; Padovese, Valeska; Folch, Cinta; et al.
Epidemiology and determinants of reemerging bacterial sexually transmitted infections (STIs) and emerging STIs in Europe Journal Article
In: The Lancet Regional Health – Europe, vol. 34, pp. 100742, 2023, ISSN: 2666-7762.
@article{MITJA2023100742,
title = {Epidemiology and determinants of reemerging bacterial sexually transmitted infections (STIs) and emerging STIs in Europe},
author = {Oriol Mitjà and Valeska Padovese and Cinta Folch and Isotta Rossoni and Michael Marks and Miquel Angel Rodríguez Arias and Amalio Telenti and Angela Ciuffi and Karel Blondeel and Otilia Mårdh and Jordi Casabona},
doi = {https://doi.org/10.1016/j.lanepe.2023.100742},
issn = {2666-7762},
year = {2023},
date = {2023-01-01},
journal = {The Lancet Regional Health - Europe},
volume = {34},
pages = {100742},
abstract = {In this scoping review, we offer a comprehensive understanding of the current and recent epidemiology, challenges, and emerging issues related to bacterial sexually transmitted infections (STIs) in the WHO European Region. We endeavour in collating data from both EU/EEA and non- EU/EEA countries, thereby giving a complete picture of the region which highlights the higher notification rates in Northern and Western countries than other regions, likely due to differences in testing, access to testing, and surveillance capacity. We provide an up-to-date review on the current knowledge of determinants and persistent inequities in key populations as well as the use of molecular epidemiology for identifying transmission networks in gonorrhoea and syphilis, and detecting chlamydia mutations that evade molecular diagnosis. Finally, we explore the emerging STIs in the region and the evolving transmission routes of food and waterborne diseases into sexual transmission. Our findings call for harmonized STI surveillance systems, proactive strategies, and policies to address social factors, and staying vigilant for emerging STIs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In this scoping review, we offer a comprehensive understanding of the current and recent epidemiology, challenges, and emerging issues related to bacterial sexually transmitted infections (STIs) in the WHO European Region. We endeavour in collating data from both EU/EEA and non- EU/EEA countries, thereby giving a complete picture of the region which highlights the higher notification rates in Northern and Western countries than other regions, likely due to differences in testing, access to testing, and surveillance capacity. We provide an up-to-date review on the current knowledge of determinants and persistent inequities in key populations as well as the use of molecular epidemiology for identifying transmission networks in gonorrhoea and syphilis, and detecting chlamydia mutations that evade molecular diagnosis. Finally, we explore the emerging STIs in the region and the evolving transmission routes of food and waterborne diseases into sexual transmission. Our findings call for harmonized STI surveillance systems, proactive strategies, and policies to address social factors, and staying vigilant for emerging STIs.
Fernández-Naval, Candela; Arando, Maider; Espasa, Mateu; et al.
Multilocus sequence typing of Treponema pallidum subsp. pallidum in Barcelona Journal Article
In: Future Microbiology, vol. 16, no. 13, pp. 967-976, 2021.
@article{Fernandez2021,
title = {Multilocus sequence typing of Treponema pallidum subsp. pallidum in Barcelona},
author = {Candela Fernández-Naval and Maider Arando and Mateu Espasa and Andrés Antón and Miguel Fernández-Huerta and Aroa Silgado and Cristina Pinatar and Francesc Zarzuela and Juan José González-López and Judit Serra-Pladevall and Elena Sulleiro and Tomàs Pumarola and Martí Vall-Mayans and Juliana Esperalba},
doi = {https://doi.org/10.2217/fmb-2021-0037},
year = {2021},
date = {2021-01-01},
journal = {Future Microbiology},
volume = {16},
number = {13},
pages = {967-976},
abstract = {Aim: To implement the multilocus sequence typing (MLST) methodology in syphilis samples previously characterized by enhanced CDC typing (ECDCT) and macrolide resistance. Materials & methods: MLST was performed on genital ulcer and blood samples by analyzing a region of the tp0136, tp0548 and tp0705 loci using Sanger sequencing. Results: Up to 59/85 (69.4%) of genital ulcer and 4/39 (10.3%) of whole blood samples were fully typed. The most frequent profiles were 1.3.1 (56%) and 1.1.1 (11%). All the 1.3.1 samples typed carried the A2058G mutation, responsible for macrolide resistance. MLST and ECDCT showed similar overall typing yields. Conclusion: Several allelic profiles of T. pallidum subsp. pallidum were identified and classified into two major genetic clades in Barcelona. Our results were similar to that described in Europe.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Aim: To implement the multilocus sequence typing (MLST) methodology in syphilis samples previously characterized by enhanced CDC typing (ECDCT) and macrolide resistance. Materials & methods: MLST was performed on genital ulcer and blood samples by analyzing a region of the tp0136, tp0548 and tp0705 loci using Sanger sequencing. Results: Up to 59/85 (69.4%) of genital ulcer and 4/39 (10.3%) of whole blood samples were fully typed. The most frequent profiles were 1.3.1 (56%) and 1.1.1 (11%). All the 1.3.1 samples typed carried the A2058G mutation, responsible for macrolide resistance. MLST and ECDCT showed similar overall typing yields. Conclusion: Several allelic profiles of T. pallidum subsp. pallidum were identified and classified into two major genetic clades in Barcelona. Our results were similar to that described in Europe.
Haynes, Austin M.; Giacani, Lorenzo; Mayans, Marti Vall; et al.
Efficacy of linezolid on textitTreponema pallidum, the syphilis agent: A preclinical study Journal Article
In: EBioMedicine, vol. 65, 2021, ISSN: 2352-3964.
@article{Haynes2021,
title = {Efficacy of linezolid on textitTreponema pallidum, the syphilis agent: A preclinical study},
author = {Austin M. Haynes and Lorenzo Giacani and Marti Vall Mayans and Maria Ubals and Carles Nieto and Clara Pérez-Mañá and Llorenç Quintó and Emily Romeis and Oriol Mitjà},
doi = {10.1016/j.ebiom.2021.103281},
issn = {2352-3964},
year = {2021},
date = {2021-01-01},
journal = {EBioMedicine},
volume = {65},
publisher = {Elsevier},
abstract = {Penicillin G, the current standard treatment for syphilis, has important drawbacks, but virtually no preclinical or clinical studies have been performed to identify viable alternatives. We tested, both textitin vitro and textitin vivo, three marketed antibiotics with adequate pharmacological properties to treat syphilis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Penicillin G, the current standard treatment for syphilis, has important drawbacks, but virtually no preclinical or clinical studies have been performed to identify viable alternatives. We tested, both textitin vitro and textitin vivo, three marketed antibiotics with adequate pharmacological properties to treat syphilis.
Hoyos-Mallecot, Yannick; Garcia, Jorge Nestor; Sulleiro, Elena; et al.
Drassanes Exprés: a public and confidential testing service for asymptomatic STIs with same-day result notification Journal Article
In: Sexually Transmitted Infections, 2021, ISSN: 1368-4973.
@article{Hoyos-Mallecotsextrans-2020-054779,
title = {Drassanes Exprés: a public and confidential testing service for asymptomatic STIs with same-day result notification},
author = {Yannick Hoyos-Mallecot and Jorge Nestor Garcia and Elena Sulleiro and Juliana Esperalba and Paula Salmeron and Francesc Zarzuela and Albert Blanco and Maider Arando and Vicente Descalzo and Luis Lopez and Martí Vall-Mayans and María Jesús Barberá and Judit Serra-Pladevall and Montserrat LLinas and Benito Almirante and Tomas Pumarola and Mateu Espasa},
doi = {10.1136/sextrans-2020-054779},
issn = {1368-4973},
year = {2021},
date = {2021-01-01},
journal = {Sexually Transmitted Infections},
publisher = {The Medical Society for the Study of Venereal Disease},
abstract = {Background STIs are a major public health concern. Screening programmes for asymptomatic users are key components of STI control. Traditional limitations of screening programmes include low population coverage and delays in treatments, thus reducing the expected impact on STI control. In our centre, the normal time from test to results was 4 days, and 7 days until treatment was established.To reduce time to treatment and to increase population coverage, we developed ‘Drassanes Exprés’, a testing service for asymptomatic STIs. The objectives of this study were to provide a guide for the implementation of a service with these characteristics and to evaluate the results of this intervention.Methods The Drassanes Exprés programme was launched in Spain on 07 November 2016 as a public, confidential and free-of-charge testing service for asymptomatic STIs, with same-day result notification. For this walk-in service, confidentiality was obtained by registering all information into the Laboratory Internal Software instead of the Electronic Patient Records. Samples were processed in a point-of-care laboratory and result notification was provided via mail or short message service.Information about workflow, screening protocols and result interpretation is detailed. Additionally, demographic characteristics, STI prevalence, and time from patients’ sample collection to notification and treatment are analysed.Results Between 07 November 2016 and 07 November 2019, 13 993 users attended the Drassanes Exprés screening programme. Of these, 0.5% were transgender people, 29.3% women, 45.2% men who have sex with men and 25.1% men who have sex with women. The median age was 31 years (range: 26–39 years). Overall, 14.6% of users tested positive for at least one STI. The most prevalent infection was Chlamydia trachomatis (8.3%), followed by Neisseria gonorrhoeae (5.7%), syphilis (1.8%), HIV (0.4%) and hepatitis C virus (0.2%). The median time from test to results was 2.4 hours (range: 2–3.1 hours). Of 2049 users diagnosed with an STI, treatment was achieved in 97.0% of cases; the average time to treatment was 2.0 days.Conclusions Drassanes Exprés is the first public programme for rapid, asymptomatic, STI screening and treatment in Spain. Assessing high-risk practices and providing confidentiality, easy access and rapid results/treatments are key elements in the development of STI screening programmes.Data are available upon reasonable request. All data relevant to the study are included in the article, however more detailed protocols are available upon request.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background STIs are a major public health concern. Screening programmes for asymptomatic users are key components of STI control. Traditional limitations of screening programmes include low population coverage and delays in treatments, thus reducing the expected impact on STI control. In our centre, the normal time from test to results was 4 days, and 7 days until treatment was established.To reduce time to treatment and to increase population coverage, we developed ‘Drassanes Exprés’, a testing service for asymptomatic STIs. The objectives of this study were to provide a guide for the implementation of a service with these characteristics and to evaluate the results of this intervention.Methods The Drassanes Exprés programme was launched in Spain on 07 November 2016 as a public, confidential and free-of-charge testing service for asymptomatic STIs, with same-day result notification. For this walk-in service, confidentiality was obtained by registering all information into the Laboratory Internal Software instead of the Electronic Patient Records. Samples were processed in a point-of-care laboratory and result notification was provided via mail or short message service.Information about workflow, screening protocols and result interpretation is detailed. Additionally, demographic characteristics, STI prevalence, and time from patients’ sample collection to notification and treatment are analysed.Results Between 07 November 2016 and 07 November 2019, 13 993 users attended the Drassanes Exprés screening programme. Of these, 0.5% were transgender people, 29.3% women, 45.2% men who have sex with men and 25.1% men who have sex with women. The median age was 31 years (range: 26–39 years). Overall, 14.6% of users tested positive for at least one STI. The most prevalent infection was Chlamydia trachomatis (8.3%), followed by Neisseria gonorrhoeae (5.7%), syphilis (1.8%), HIV (0.4%) and hepatitis C virus (0.2%). The median time from test to results was 2.4 hours (range: 2–3.1 hours). Of 2049 users diagnosed with an STI, treatment was achieved in 97.0% of cases; the average time to treatment was 2.0 days.Conclusions Drassanes Exprés is the first public programme for rapid, asymptomatic, STI screening and treatment in Spain. Assessing high-risk practices and providing confidentiality, easy access and rapid results/treatments are key elements in the development of STI screening programmes.Data are available upon reasonable request. All data relevant to the study are included in the article, however more detailed protocols are available upon request.
