Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division
Acinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed....
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.967949/full |
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| author | Wern Chern Chai Jonathan J. Whittall Steven W. Polyak Klyie Foo Xin Li Cameron J. Dutschke Abiodun D. Ogunniyi Shutao Ma Matthew J. Sykes Susan J. Semple Susan J. Semple Henrietta Venter |
| author_facet | Wern Chern Chai Jonathan J. Whittall Steven W. Polyak Klyie Foo Xin Li Cameron J. Dutschke Abiodun D. Ogunniyi Shutao Ma Matthew J. Sykes Susan J. Semple Susan J. Semple Henrietta Venter |
| author_sort | Wern Chern Chai |
| collection | DOAJ |
| description | Acinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed. The bacterial cell division protein, FtsZ, is a promising drug target for the development of novel antimicrobial agents. We have previously reported limited activity of cinnamaldehyde analogs against Escherichia coli. In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against A. baumannii. Microscopic analysis was performed to determine if the compounds inhibit cell division. The on-target effect of the compounds was assessed by analyzing their effect on polymerization and on the GTPase activity of purified FtsZ from A. baumannii. In silico docking was used to assess the binding of cinnamaldehyde analogs. Finally, in vivo and in vitro safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen A. baumannii, with 4-bromophenyl-substituted 4 displaying the most potent antimicrobial activity (MIC 32 μg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for A. baumannii ATCC 19606 (up to 32-fold) and significantly, for extensively drug resistant UW 5075 (greater than 4-fold), suggesting that efflux contributes to the intrinsic resistance of A. baumannii against these agents. The compounds inhibited cell division in A. baumannii as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity. In silico docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated 6 was devoid of hemolytic activity and cytotoxicity against mammalian cells in vitro, as well as adverse activity in a Caenorhabditis elegans nematode model in vivo. Together, these findings present halogenated analogs 4 and 6 as promising candidates for further development as antimicrobial agents aimed at combating A. baumannii. This is also the first report of FtsZ-targeting compounds with activity against an XDR A. baumannii strain. |
| first_indexed | 2024-12-10T19:32:19Z |
| format | Article |
| id | doaj.art-1275ad5db29a4c3abb2e70da30457d33 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-10T19:32:19Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-1275ad5db29a4c3abb2e70da30457d332022-12-22T01:36:13ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-08-011310.3389/fmicb.2022.967949967949Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell divisionWern Chern Chai0Jonathan J. Whittall1Steven W. Polyak2Klyie Foo3Xin Li4Cameron J. Dutschke5Abiodun D. Ogunniyi6Shutao Ma7Matthew J. Sykes8Susan J. Semple9Susan J. Semple10Henrietta Venter11Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, ChinaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaAustralian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, SA, AustraliaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, ChinaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaQuality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, AustraliaAcinetobacter baumannii is a pathogen with high intrinsic antimicrobial resistance while multidrug resistant (MDR) and extensively drug resistant (XDR) strains of this pathogen are emerging. Treatment options for infections by these strains are very limited, hence new therapies are urgently needed. The bacterial cell division protein, FtsZ, is a promising drug target for the development of novel antimicrobial agents. We have previously reported limited activity of cinnamaldehyde analogs against Escherichia coli. In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against A. baumannii. Microscopic analysis was performed to determine if the compounds inhibit cell division. The on-target effect of the compounds was assessed by analyzing their effect on polymerization and on the GTPase activity of purified FtsZ from A. baumannii. In silico docking was used to assess the binding of cinnamaldehyde analogs. Finally, in vivo and in vitro safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen A. baumannii, with 4-bromophenyl-substituted 4 displaying the most potent antimicrobial activity (MIC 32 μg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for A. baumannii ATCC 19606 (up to 32-fold) and significantly, for extensively drug resistant UW 5075 (greater than 4-fold), suggesting that efflux contributes to the intrinsic resistance of A. baumannii against these agents. The compounds inhibited cell division in A. baumannii as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity. In silico docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated 6 was devoid of hemolytic activity and cytotoxicity against mammalian cells in vitro, as well as adverse activity in a Caenorhabditis elegans nematode model in vivo. Together, these findings present halogenated analogs 4 and 6 as promising candidates for further development as antimicrobial agents aimed at combating A. baumannii. This is also the first report of FtsZ-targeting compounds with activity against an XDR A. baumannii strain.https://www.frontiersin.org/articles/10.3389/fmicb.2022.967949/fullantimicrobial resistanceantimicrobial drug developmentFtsZFtsZ inhibitorcinnamaldehydegram-negative |
| spellingShingle | Wern Chern Chai Jonathan J. Whittall Steven W. Polyak Klyie Foo Xin Li Cameron J. Dutschke Abiodun D. Ogunniyi Shutao Ma Matthew J. Sykes Susan J. Semple Susan J. Semple Henrietta Venter Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division Frontiers in Microbiology antimicrobial resistance antimicrobial drug development FtsZ FtsZ inhibitor cinnamaldehyde gram-negative |
| title | Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division |
| title_full | Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division |
| title_fullStr | Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division |
| title_full_unstemmed | Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division |
| title_short | Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division |
| title_sort | cinnamaldehyde derivatives act as antimicrobial agents against acinetobacter baumannii through the inhibition of cell division |
| topic | antimicrobial resistance antimicrobial drug development FtsZ FtsZ inhibitor cinnamaldehyde gram-negative |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.967949/full |
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