Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function
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| Title: | Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Staphylococcus aureus Growth Independent of LtaS Function |
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| Authors: | Edward J. A. Douglas, Brandon Marshall, Arwa Alghamadi, Erin A. Joseph, Seána Duggan, Serena Vittorio, Laura De Luca, Michaela Serpi, Maisem Laabei |
| Source: | ACS Infect Dis |
| Publisher Information: | American Chemical Society (ACS), 2023. |
| Publication Year: | 2023 |
| Subject Terms: | 0301 basic medicine, Mammals, Methicillin-Resistant Staphylococcus aureus, 0303 health sciences, Oxadiazoles, Staphylococcus aureus, Anti-Bacterial Agents/chemistry, Staphylococcal Infections, Oxadiazoles/pharmacology, 3. Good health, Anti-Bacterial Agents, Staphylococcal Infections/microbiology, 03 medical and health sciences, 1,3,4 oxadiazole, Staphylococcus aureus, antimicrobial resistance, drug discovery, lipoteichoic acid inhibitors, Animals |
| Description: | The lipoteichoic acid (LTA) biosynthesis pathway has emerged as a promising antimicrobial therapeutic target. Previous studies identified the 1,3,4 oxadiazole compound 1771 as an LTA inhibitor with activity against Gram-positive pathogens. We have succeeded in making six 1771 derivatives and, through subsequent hit validation, identified the incorporation of a pentafluorosulfanyl substituent as central in enhancing activity. Our newly described derivative, compound 13, showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant Staphylococcus aureus strains while simultaneously exhibiting an improved toxicity profile against mammalian cells. Molecular techniques were employed in which the assumed target, lipoteichoic acid synthase (LtaS), was both deleted and overexpressed. Neither deletion nor overexpression of LtaS altered 1771 or compound 13 susceptibility; however, overexpression of LtaS increased the MIC of Congo red, a previously identified LtaS inhibitor. These data were further supported by comparing the docking poses of 1771 and derivatives in the LtaS active site, which indicated the possibility of an additional target(s). Finally, we show that both 1771 and compound 13 have activity that is independent of LtaS, extending to cover Gram-negative species if the outer membrane is first permeabilized, challenging the classification that these compounds are strict LtaS inhibitors. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.3c00250 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/37828912 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10644342/ https://hdl.handle.net/11570/3294569 https://doi.org/10.1021/acsinfecdis.3c00250 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (http://creativecommons.org/licenses/by/4.0/). |
| Accession Number: | edsair.doi.dedup.....ff28a346a0ba8cc1c9ea44315a9e9fdb |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | The lipoteichoic acid (LTA) biosynthesis pathway has emerged as a promising antimicrobial therapeutic target. Previous studies identified the 1,3,4 oxadiazole compound 1771 as an LTA inhibitor with activity against Gram-positive pathogens. We have succeeded in making six 1771 derivatives and, through subsequent hit validation, identified the incorporation of a pentafluorosulfanyl substituent as central in enhancing activity. Our newly described derivative, compound 13, showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant Staphylococcus aureus strains while simultaneously exhibiting an improved toxicity profile against mammalian cells. Molecular techniques were employed in which the assumed target, lipoteichoic acid synthase (LtaS), was both deleted and overexpressed. Neither deletion nor overexpression of LtaS altered 1771 or compound 13 susceptibility; however, overexpression of LtaS increased the MIC of Congo red, a previously identified LtaS inhibitor. These data were further supported by comparing the docking poses of 1771 and derivatives in the LtaS active site, which indicated the possibility of an additional target(s). Finally, we show that both 1771 and compound 13 have activity that is independent of LtaS, extending to cover Gram-negative species if the outer membrane is first permeabilized, challenging the classification that these compounds are strict LtaS inhibitors. |
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| ISSN: | 23738227 |
| DOI: | 10.1021/acsinfecdis.3c00250 |