Cinnamaldehyde derivatives act as antimicrobial agents against Acinetobacter baumannii through the inhibition of cell division
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 divis...
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| Published in: | Frontiers in microbiology Vol. 13; p. 967949 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Switzerland
Frontiers Media S.A
29-08-2022
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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
. In this study, we have determined the antimicrobial activity of six cinnamaldehyde analogs for antimicrobial activity against
. 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
.
docking was used to assess the binding of cinnamaldehyde analogs. Finally,
and
safety assays were performed. All six compounds displayed antibacterial activity against the critical priority pathogen
, with 4-bromophenyl-substituted
displaying the most potent antimicrobial activity (MIC 32 μg/mL). Bioactivity was significantly increased in the presence of an efflux pump inhibitor for
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
against these agents. The compounds inhibited cell division in
as observed by the elongated phenotype and targeted the FtsZ protein as seen from the inhibition of polymerization and GTPase activity.
docking predicted that the compounds bind in the interdomain cleft adjacent to the H7 core helix. Di-chlorinated
was devoid of hemolytic activity and cytotoxicity against mammalian cells
, as well as adverse activity in a
nematode model
. Together, these findings present halogenated analogs
and
as promising candidates for further development as antimicrobial agents aimed at combating
. This is also the first report of FtsZ-targeting compounds with activity against an XDR
strain. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Orietta Massidda, University of Trento, Italy; Tomás Subils, CONICET Rosario, Argentina Edited by: Silvia Buroni, University of Pavia, Italy This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology |
| ISSN: | 1664-302X 1664-302X |
| DOI: | 10.3389/fmicb.2022.967949 |