TY - JOUR
T1 - Dysregulation of Mycobacterium marinum ESX-5 Secretion by Novel 1,2,4-oxadiazoles
AU - Ho, Vien Q.T.
AU - Rong, Mark K.
AU - Habjan, Eva
AU - Bommer, Samantha D.
AU - Pham, Thang V.
AU - Piersma, Sander R.
AU - Bitter, Wilbert
AU - Ruijter, Eelco
AU - Speer, Alexander
N1 - Funding Information: This study was funded by the Netherlands Organization for Scientific Research (NWO) through TTW-NACTAR-18508 and TTW-NACTAR-16445 granted to A.S., E.R., and W.B. Publisher Copyright: © 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - The ESX-5 secretion system is essential for the viability and virulence of slow-growing pathogenic mycobacterial species. In this study, we identified a 1,2,4-oxadiazole derivative as a putative effector of the ESX-5 secretion system. We confirmed that this 1,2,4-oxadiazole and several newly synthesized derivatives inhibited the ESX-5-dependent secretion of active lipase LipY by Mycobacterium marinum (M. marinum). Despite reduced lipase activity, we did not observe a defect in LipY secretion itself. Moreover, we found that several other ESX-5 substrates, especially the high molecular-weight PE_PGRS MMAR_5294, were even more abundantly secreted by M. marinum treated with several 1,2,4-oxadiazoles. Analysis of M. marinum grown in the presence of different oxadiazole derivatives revealed that the secretion of LipY and the induction of PE_PGRS secretion were, in fact, two independent phenotypes, as we were able to identify structural features in the compounds that specifically induced only one of these phenotypes. Whereas the three most potent 1,2,4-oxadiazoles displayed only a mild effect on the growth of M. marinum or M. tuberculosis in culture, these compounds significantly reduced bacterial burden in M. marinum-infected zebrafish models. In conclusion, we report a 1,2,4-oxadiazole scaffold that dysregulates ESX-5 protein secretion.
AB - The ESX-5 secretion system is essential for the viability and virulence of slow-growing pathogenic mycobacterial species. In this study, we identified a 1,2,4-oxadiazole derivative as a putative effector of the ESX-5 secretion system. We confirmed that this 1,2,4-oxadiazole and several newly synthesized derivatives inhibited the ESX-5-dependent secretion of active lipase LipY by Mycobacterium marinum (M. marinum). Despite reduced lipase activity, we did not observe a defect in LipY secretion itself. Moreover, we found that several other ESX-5 substrates, especially the high molecular-weight PE_PGRS MMAR_5294, were even more abundantly secreted by M. marinum treated with several 1,2,4-oxadiazoles. Analysis of M. marinum grown in the presence of different oxadiazole derivatives revealed that the secretion of LipY and the induction of PE_PGRS secretion were, in fact, two independent phenotypes, as we were able to identify structural features in the compounds that specifically induced only one of these phenotypes. Whereas the three most potent 1,2,4-oxadiazoles displayed only a mild effect on the growth of M. marinum or M. tuberculosis in culture, these compounds significantly reduced bacterial burden in M. marinum-infected zebrafish models. In conclusion, we report a 1,2,4-oxadiazole scaffold that dysregulates ESX-5 protein secretion.
KW - ESX-5
KW - Mycobacterium marinum
KW - mycobacteria
KW - protein secretion
KW - type VII secretion
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U2 - https://doi.org/10.3390/biom13020211
DO - https://doi.org/10.3390/biom13020211
M3 - Article
C2 - 36830581
SN - 2218-273X
VL - 13
SP - 1
EP - 14
JO - BIOMOLECULES
JF - BIOMOLECULES
IS - 2
M1 - 211
ER -