2026-04-19T22:14:36Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/1960062025-12-05T14:25:56Zcom_2072_1057col_2072_478816col_2072_478917
RECERCAT author Stampolaki, Marianna author Malwal, Satish R. author Álvarez-Cabrera, Nadine author Gao, Zijun author Moniruzzaman, Mohammad author Babii, Svitlana O. author Naziris, Nikolaos author Rey-Cibati, André author Valladares-Delgado, Mariana author Turcu, Andreea L. author Baek, Kyung-Hwa author Phan, Trong-Nhat author Lee, Hyeryon author Alcaraz, Mattheo author Watson, Savannah author Van der Watt, Mariette author Coertzen, Dina author Efstathiou, Natasa author Chountoulesi, Maria author Shoen, Carolyn M. author Papanastasiou, Ioannis P. author Brea, José author Cynamon, Michael H. author Birkholtz, Lyn-Marié author Kremer, Laurent author Hwan No, Joo author Vázquez Cruz, Santiago author Benaim, Gustavo author Demetzos, Costas author Zgurskaya, Helen I. author Dick, Thomas author Oldfield, Eric author Kolocouris, Antonios 2023-03-27T10:18:14Z2024-03-27T06:10:10Z2023-03-272023-03-27T10:18:14Z SQ109 is a tuberculosis drug candidate that has high potency against Mycobacterium tuberculosis and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca2+ homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against M. smegmatis, M. tuberculosis, M. abscessus, Bacillus subtilis, and Escherichia coli, as well as against the protozoan parasites Trypanosoma brucei, T. cruzi, Leishmania donovani, L. mexicana, and Plasmodium falciparum. Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ∼4−8-fold more active than SQ109 against M. abscessus, including a highly drugresistant strain harboring an A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl, and benzyl analogs had 4−10× increased activity against P. falciparum asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new antimalarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3 and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and M. tuberculosis or M. smegmatis cell activity, suggesting that MmpL3 is not a major target in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, which is expected to lead to enhanced uncoupler activity. (c) American Chemical Society , 2023 info:eu-repo/semantics/openAccess Tuberculosi Malària Leishmaniosi Tuberculosis Malaria Leishmaniasis Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against Mycobacterium abscessus and Malaria Parasites info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion