Thesis title: Development of Novel Antimalarial Transmission Blocking Agents and Genetic Characterization of Drug Resistance in Mycobacterium abscessus
The discovery and development of novel compounds and innovative therapeutic strategies for infectious diseases remain a formidable challenge due to the rising of drug resistance. This thesis explores this challenge through the development of antimalarial transmission-blocking agents and the characterization of genes contributing to drug resistance in Mycobacterium abscessus. Malaria remains a global health emergency, with progress in combating the disease stagnating, particularly due to the pandemic COVID-19. The most virulent species, Plasmodium falciparum, has a life cycle involving both mosquitoes
(sexual stages) and humans (asexual and sexual stages). The WHO's goal of reducing malaria incidence by 89% by 2030 appears increasingly difficult due to
rising resistance of Plasmodium to common antimalarial treatments. Therefore, there is a critical need to develop novel compounds targeting the sexual stages of the parasite's lifecycle to address resistance mechanisms in the asexual stages, which are the primary targets of conventional antimalarial drugs. Transmission blocking compounds that inhibit parasite development in both human hosts and mosquito vectors offer a promising approach. Pursuing this aim, we synthesized analogues of MMV1580843, identified in a high-throughput screening as a potent and selective gametocytocidal compound. The goal of this PhD thesis is to design and synthesize new pyrrole- and imidazole-based derivatives by modifying the substitutions around the central core, to enhance transmission-blocking activity. Infections caused by non-tuberculous mycobacteria, particularly Mycobacterium abscessus (Mab), continue to present significant therapeutic challenges due to intrinsic resistance to most antibiotics. Mab is an opportunistic pathogen responsible for severe pulmonary infections, especially in immunocompromised individuals. This study aimed to identify potential therapeutic targets to enhance the efficacy of Bedaquiline and SQ109, by performing transposon mutagenesis and sequencing screen (TnSeq). The focus was on discovering conditionally essential genes that may play a critical role under host-like conditions, compared to those identified in standard culture media. To simulate a host-like environment, we developed an in vitro infection model using air-liquid interface (ALI) culture. This approach aims to uncover potential targets for improving treatment strategies against Mab and addressing the growing threat of this challenging pathogen.