Periodic Reporting for period 2 - Trep-AB (Repurposing clinically approved antibacterial drugs for treponematoses therapy)
Période du rapport: 2021-08-01 au 2023-01-31
Current therapeutic options for human treponematoses, syphilis and yaws, are, broadly speaking, restricted to one antibiotic: injectable penicillin. The drug susceptibility profile of Treponema pallidum (T.p) is unknown because the microorganism could not be grown in culture. Treatment failure after penicillin has been related to syphilis bacteria that survive in the central nervous system (CNS) and the potential of strains to acquire resistance to penicillin has recently been recognized. Yaws can be treated with azithromycin but there is a real risk that macrolide-resistant strains disseminate widely and jeopardize the global eradication campaign. I propose a research program to have other validated treatment options with good CNS penetration that are efficacious for all the stages of treponemal
infection. Our preliminary results using computational prediction of drug activity based on similarity to drugs with known activity against T.p. and other spirochetes shows several candidate antibiotics. New antibacterial oral drugs for the treatment of treponematoses will be a tremendous resource in case of penicillin treatment-failure, resistance, shortage, allergy, or for use in yaws combination regimens to reduce the likelihood of resistance selection.
If successful, our project will determine the efficacy of new antibacterial drugs with good CNS penetration for the treatment of syphilis. New antibacterial agents would be used when penicillin fails to treat the infection, in the context of the shortages of penicillin-G-benzathine which expose patients to suboptimal curative options for this disease and would be a valuable alternative to those allergic to penicillin. In addition, new treatment regimens have the potential to increase the patients’ likelihood to be cured of syphilis because switching from an injectable formulation to an oral one will improve convenience and patient acceptance of treatment. The discovery of new effective antibiotics has the potential to change treatment policies worldwide. Furthermore, because of the growing concern with antimicrobial resistance, new antibiotic regimens could be used in combination drug therapy with penicillin as a resistance management strategy. This is particularly important in the case of yaws where combined treatment by MDA is the most effective way to achieve disease eradication.
The overarching idea of the work proposed herein is to investigate the application of existing drugs to treponemal diseases. The main goal of the project is to provide strong evidence supporting (or rejecting) the
hypothesis that the use of an antibiotic delivered as an oral short-course (or single dose) to patients with syphilis/yaws (who are followed for 12 calendar months thereafter), can cure the disease as corroborated by molecular methods. Such study conducted as a RCT will incorporate the possibility of in-depth studying any syphilis/yaws recurrent events among study participants, so as to further clarify the biological basis.
infection. Our preliminary results using computational prediction of drug activity based on similarity to drugs with known activity against T.p. and other spirochetes shows several candidate antibiotics. New antibacterial oral drugs for the treatment of treponematoses will be a tremendous resource in case of penicillin treatment-failure, resistance, shortage, allergy, or for use in yaws combination regimens to reduce the likelihood of resistance selection.
If successful, our project will determine the efficacy of new antibacterial drugs with good CNS penetration for the treatment of syphilis. New antibacterial agents would be used when penicillin fails to treat the infection, in the context of the shortages of penicillin-G-benzathine which expose patients to suboptimal curative options for this disease and would be a valuable alternative to those allergic to penicillin. In addition, new treatment regimens have the potential to increase the patients’ likelihood to be cured of syphilis because switching from an injectable formulation to an oral one will improve convenience and patient acceptance of treatment. The discovery of new effective antibiotics has the potential to change treatment policies worldwide. Furthermore, because of the growing concern with antimicrobial resistance, new antibiotic regimens could be used in combination drug therapy with penicillin as a resistance management strategy. This is particularly important in the case of yaws where combined treatment by MDA is the most effective way to achieve disease eradication.
The overarching idea of the work proposed herein is to investigate the application of existing drugs to treponemal diseases. The main goal of the project is to provide strong evidence supporting (or rejecting) the
hypothesis that the use of an antibiotic delivered as an oral short-course (or single dose) to patients with syphilis/yaws (who are followed for 12 calendar months thereafter), can cure the disease as corroborated by molecular methods. Such study conducted as a RCT will incorporate the possibility of in-depth studying any syphilis/yaws recurrent events among study participants, so as to further clarify the biological basis.
From the beginning of the period:
IN PRECLINICAL STUDIES
1) we completed the testing of clinically approved (or currently in Phase III clinical trials, like zoliflodacin) antimicrobials in vitro against the syphilis agent.
2) completed the testing of Azithromycin to evaluate whether genetic resistance could be overcome by increased antibiotic concentration and completed the series of long-term propagation of T. pallidum in presence of sub-therapeutic concentrations of Linezolid
3) performed toxicity assays on the eukaryotic cells (rabbis Sf1Ep cells) that support treponemal growth in vitro to demonstrate that when a tested antibiotic was effec-tive against the syphilis agent, such efficacy was not due to toxicity against the eukaryotic cells in vitro. Results support that cefuroxime, tedizolid, cefetamet, ce-falexin, cefixime, and dalbavancin are treponemicidal in vitro.
4) performed whole genome sequence of the strain exposed to the antibiotic, as well as a new in vitro susceptibility test, and demonstrated that no mutations were pre-sent that could be related to development of linezolid resistance, and that the strain propagated in sub-therapeutic linezolid remained as sensitive to the antibiotic as the wild type
INTERVENTIONAL STUDIES
5) we designed, obtained authorizations and started the implementation of an open-label, non-inferiority, two-armed RCT comparing the identified investigational antibiotic linezolid to standard intramuscular long-acting penicillin (C) to treat patients with syphilis in the Barcelona area (Spain)
6) we designed and obtained authorizations for an open-label, non-inferiority, two-armed RCT comparing the identified investigational antibiotic linezolid to standard intramuscular long-acting penicillin (C) to treat patients with yaws in a yet to be defined insular region of Papua New Guinea
IN PRECLINICAL STUDIES
1) we completed the testing of clinically approved (or currently in Phase III clinical trials, like zoliflodacin) antimicrobials in vitro against the syphilis agent.
2) completed the testing of Azithromycin to evaluate whether genetic resistance could be overcome by increased antibiotic concentration and completed the series of long-term propagation of T. pallidum in presence of sub-therapeutic concentrations of Linezolid
3) performed toxicity assays on the eukaryotic cells (rabbis Sf1Ep cells) that support treponemal growth in vitro to demonstrate that when a tested antibiotic was effec-tive against the syphilis agent, such efficacy was not due to toxicity against the eukaryotic cells in vitro. Results support that cefuroxime, tedizolid, cefetamet, ce-falexin, cefixime, and dalbavancin are treponemicidal in vitro.
4) performed whole genome sequence of the strain exposed to the antibiotic, as well as a new in vitro susceptibility test, and demonstrated that no mutations were pre-sent that could be related to development of linezolid resistance, and that the strain propagated in sub-therapeutic linezolid remained as sensitive to the antibiotic as the wild type
INTERVENTIONAL STUDIES
5) we designed, obtained authorizations and started the implementation of an open-label, non-inferiority, two-armed RCT comparing the identified investigational antibiotic linezolid to standard intramuscular long-acting penicillin (C) to treat patients with syphilis in the Barcelona area (Spain)
6) we designed and obtained authorizations for an open-label, non-inferiority, two-armed RCT comparing the identified investigational antibiotic linezolid to standard intramuscular long-acting penicillin (C) to treat patients with yaws in a yet to be defined insular region of Papua New Guinea
This proposal challenges the current view that penicillin is the best possible treatment for T.p infections, and that the bacteria will continue to exhibit complete sensitivity to penicillin in the future. Since penicillin became
available in the 1940’s the research on development of new antimicrobials or evaluation of existing antimicrobials for treponemal diseases has been almost non-existent. One exception are trials done to test azithromycin, but macrolide resistance has unfortunately been documented in many countries and macrolides are not currently recommended for treatment of syphilis. The evidence for other non-penicillin treatment of syphilis consists mostly of small, uncontrolled, retrospective studies. Research on syphilis has traditionally focused on the use of penicillin and the dosage, formulation, and duration of treatment required depending upon (1) the stage of disease, (2) whether or not infection involves "protected sites" (e.g. neuro- and ocular syphilis), (3) management of treatment when there is non-serologic response, (4) repeated infection, and (5) infection in persons living with HIV. Research has also focused on the evaluation of markers to identify patients with higher risk of CNS complications and situations when lumbar puncture (LP) to test for neurosyphilis should be performed in the absence of neurological symptoms.
If successful, research on other antimicrobials with a good CNS penetration may represent a paradigm shift towards an efficacious antibiotic for all the stages of treponemal infections and host statuses that
prevents the increasing complexity of Clinical Decision Support Algorithms. Additional impacts of our research would be the identification of antimicrobials with (1) good oral absorption to decrease the complexity
of parenteral administration of penicillin, (2) alternative mechanism of action to treat the potentially emergent penicillin-resistant form that could make syphilis, a potentially fatal Sexually Transmitted Infection (STI),
even harder to treat, (3) alternative drug to effectively treat syphilis in the event of shortages of penicillin-Gbenzathine, (4) alternative drug to treat patients that are allergic to penicillin.
available in the 1940’s the research on development of new antimicrobials or evaluation of existing antimicrobials for treponemal diseases has been almost non-existent. One exception are trials done to test azithromycin, but macrolide resistance has unfortunately been documented in many countries and macrolides are not currently recommended for treatment of syphilis. The evidence for other non-penicillin treatment of syphilis consists mostly of small, uncontrolled, retrospective studies. Research on syphilis has traditionally focused on the use of penicillin and the dosage, formulation, and duration of treatment required depending upon (1) the stage of disease, (2) whether or not infection involves "protected sites" (e.g. neuro- and ocular syphilis), (3) management of treatment when there is non-serologic response, (4) repeated infection, and (5) infection in persons living with HIV. Research has also focused on the evaluation of markers to identify patients with higher risk of CNS complications and situations when lumbar puncture (LP) to test for neurosyphilis should be performed in the absence of neurological symptoms.
If successful, research on other antimicrobials with a good CNS penetration may represent a paradigm shift towards an efficacious antibiotic for all the stages of treponemal infections and host statuses that
prevents the increasing complexity of Clinical Decision Support Algorithms. Additional impacts of our research would be the identification of antimicrobials with (1) good oral absorption to decrease the complexity
of parenteral administration of penicillin, (2) alternative mechanism of action to treat the potentially emergent penicillin-resistant form that could make syphilis, a potentially fatal Sexually Transmitted Infection (STI),
even harder to treat, (3) alternative drug to effectively treat syphilis in the event of shortages of penicillin-Gbenzathine, (4) alternative drug to treat patients that are allergic to penicillin.