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Project
Understanding and preventing the emergence of antimicrobial resistance in Neisseria gonorrhoeae
Alternative strategies to prevent and contain Neisseria gonorrhoeae (NG) resistance are urgently required. This study aims to contribute to this process by achieving a better understanding of the factors underpinning the emergence of resistance in core-groups and developing new treatment options to prevent and contain the emergence of multi drug resistant (MDR) and extensively resistant (XDR) NG.
Generating and evaluating antibiotic sparing therapies
If we could treat and/or prevent NG and other STIs with non-antibiotic compounds, this would reduce the selection pressure towards antibiotic resistance. To this end we will assess the efficacy of Listerine and chlorhexidine mouthwashes in eradicating isolated pharyngeal gonorrhoea and develop bacteriophage cocktails that can in-vitro inhibit the growth of circulating and XDR NG.
Four objectives will be addressed:
1. To describe evolution of azithromycin resistance in Neisseria gonorrhoeae (NG)
a. To construct and optimize a NG Morbidostat: a bioreactor that continuously monitors bacterial growth and adjusts antibiotic concentration to induce bacterial resistance against the drug.
b. To investigate the molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae: morbidostat experiment in combination with whole genome sequencing analysis.
2. To isolate bacteriophages effective against circulating NG strains: There is increasing interest in using bacteriophages to prevent and contain the emergence of antibiotic resistance. Although bacteriophages have been shown to be active against other Neisseria species and prophages have been detected in the NG genome, we could find no evidence of any research to develop bacteriophages directed towards NG. We aim to develop a cocktail of phages active against currently circulating strains of NG in Belgium and resistant NG.
3. To investigate antimicrobial resistance in commensal Neisseria and its effect on NG
a. The effect of antibiotic use on the sensitivity of several antibiotics in commensal Neisseria in clinical samples of MSM.
b. Transformation of resistance: exploring if NG is capable to acquire resistance to certain antibiotics (azithromycin) from (commensal) Neisseria strains via the mechanism of horizontal gene transfer. If transformation is successful, we can test if the addition of DNA extracts from the microbiomes of participants recently treated with antibiotics (3.a) accelerates the development of antimicrobial resistance using the NG-morbidostat.
4. Evolution of Listerine and Chlorhexidine resistance in de NG morbidostat In our team, the hypothesis that mouthwashes can prevent or eradicate pharyngeal NG will be tested. In this context, we want to evaluate the consequences of mouthwashes as alternative treatments for pharyngeal NG. Therefore, we will attempt to induce resistance to Listerine and Chlorhexidine in the NG-optimized morbidostat. If we induce resistance (confirmed by MIC determinations), we will compare the evolved genomes to the wild-type baseline genome using whole genome sequencing. Comparative genomics will help to evaluate which mutations are associated with Listerine and chlorhexidine resistance. We will also assess if resistant strains exhibit cross resistance to commonly used antimicrobials using.
Generating and evaluating antibiotic sparing therapies
If we could treat and/or prevent NG and other STIs with non-antibiotic compounds, this would reduce the selection pressure towards antibiotic resistance. To this end we will assess the efficacy of Listerine and chlorhexidine mouthwashes in eradicating isolated pharyngeal gonorrhoea and develop bacteriophage cocktails that can in-vitro inhibit the growth of circulating and XDR NG.
Four objectives will be addressed:
1. To describe evolution of azithromycin resistance in Neisseria gonorrhoeae (NG)
a. To construct and optimize a NG Morbidostat: a bioreactor that continuously monitors bacterial growth and adjusts antibiotic concentration to induce bacterial resistance against the drug.
b. To investigate the molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae: morbidostat experiment in combination with whole genome sequencing analysis.
2. To isolate bacteriophages effective against circulating NG strains: There is increasing interest in using bacteriophages to prevent and contain the emergence of antibiotic resistance. Although bacteriophages have been shown to be active against other Neisseria species and prophages have been detected in the NG genome, we could find no evidence of any research to develop bacteriophages directed towards NG. We aim to develop a cocktail of phages active against currently circulating strains of NG in Belgium and resistant NG.
3. To investigate antimicrobial resistance in commensal Neisseria and its effect on NG
a. The effect of antibiotic use on the sensitivity of several antibiotics in commensal Neisseria in clinical samples of MSM.
b. Transformation of resistance: exploring if NG is capable to acquire resistance to certain antibiotics (azithromycin) from (commensal) Neisseria strains via the mechanism of horizontal gene transfer. If transformation is successful, we can test if the addition of DNA extracts from the microbiomes of participants recently treated with antibiotics (3.a) accelerates the development of antimicrobial resistance using the NG-morbidostat.
4. Evolution of Listerine and Chlorhexidine resistance in de NG morbidostat In our team, the hypothesis that mouthwashes can prevent or eradicate pharyngeal NG will be tested. In this context, we want to evaluate the consequences of mouthwashes as alternative treatments for pharyngeal NG. Therefore, we will attempt to induce resistance to Listerine and Chlorhexidine in the NG-optimized morbidostat. If we induce resistance (confirmed by MIC determinations), we will compare the evolved genomes to the wild-type baseline genome using whole genome sequencing. Comparative genomics will help to evaluate which mutations are associated with Listerine and chlorhexidine resistance. We will also assess if resistant strains exhibit cross resistance to commonly used antimicrobials using.
Date:12 Jan 2021 → 24 Feb 2023
Keywords:B780-tropical-medicine
Project type:PhD project