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

被引:0
|
作者
Stampolaki, Marianna [1 ]
Malwal, Satish R. [2 ]
Alvarez-Cabrera, Nadine [3 ]
Gao, Zijun [2 ]
Moniruzzaman, Mohammad [2 ]
Babii, Svitlana O. [2 ]
Naziris, Nikolaos [4 ]
Rey-Cibati, Andre [5 ]
Valladares-Delgado, Mariana [5 ]
Turcu, Andreea L. [6 ,7 ]
Baek, Kyung-Hwa [8 ]
Phan, Trong-Nhat [8 ]
Lee, Hyeryon [8 ]
Alcaraz, Mattheo [9 ]
Watson, Savannah [10 ]
van der Watt, Mariette
Coertzen, Dina [10 ]
Efstathiou, Natasa [1 ]
Chountoulesi, Maria [4 ]
Shoen, Carolyn M. [11 ]
Papanastasiou, Ioannis P. [1 ]
Brea, Jose
Cynamon, Michael H. [11 ]
Birkholtz, Lyn-Marie [10 ]
Kremer, Laurent [9 ,12 ]
No, Joo Hwan [8 ]
Vazquez, Santiago [6 ,7 ]
Benaim, Gustavo [5 ]
Demetzos, Costas [4 ]
Zgurskaya, Helen I. [2 ]
Dick, Thomas [3 ]
Oldfield, Eric [2 ]
Kolocouris, Antonios D. [1 ]
机构
[1] Natl & Kapodistrian Univ Athens, Dept Pharm, Sect Pharmaceut Chem, Lab Med Chem, Athens 15771, Greece
[2] Univ Illinois, Dept Chem, Urbana, IL 61801 USA
[3] Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ 07110 USA
[4] Natl & Kapodistrian Univ Athens, Fac Pharm, Sect Pharmaceut Technol, Athens 15771, Greece
[5] Univ Cent Venezuela UCV, Fac Ciencias, Inst Estudios Avanzados, Venezuela Inst Biolog Expt, Caracas 1050, Venezuela
[6] Univ Barcelona, Dept Farmacol Toxicol & Quim Terapeut, Lab Quim Farmaceut, Fac Farma Ciencies Alimentacio, E-08028 Barcelona, Spain
[7] Univ Barcelona, Inst Biomed IBUB, E-08028 Barcelona, Spain
[8] Inst Pasteur Korea, Host Parasite Res Lab, Seongnam Si 13488, South Korea
[9] Univ Montpellier, Inst Rech Infectiol Montpellier, CNRS UMR9004, F-34293 Montpellier, France
[10] Univ Pretoria, Inst Sustainable Malaria Control, Dept Biochem Genet & Microbiol, ZA-0028 Pretoria, South Africa
[11] Vet Affairs Med Ctr, Cent New York Res Corp, Syracuse, NY 13210 USA
[12] INSERM, IRIM, F-34965 Montpellier, France
来源
ACS INFECTIOUS DISEASES | 2023年 / 9卷 / 02期
基金
新加坡国家研究基金会; 英国医学研究理事会;
关键词
tuberculosis; malaria; leishmaniasis; antibiotic; synthesis; calorimetry; MEMBRANE TRANSPORTER; INHIBITION; DISCOVERY; MMPL3; PHARMACOKINETICS; METABOLISM; MECHANISM; GROWTH;
D O I
10.1021/acsinfecdis.2c00537342
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 similar to 4-8-fold more active than SQ109 against M. abscessus, including a highly drug-resistant 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 4-10x 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.
引用
收藏
页码:342 / 364
页数:23
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