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1,2,4-Triazolidine-3-thiones Have Specific Activity against Acinetobacter baumannii among Common Nosocomial Pathogens.
ACS Infect Dis. 2017 01 13; 3(1):62-71.AI

Abstract

Acinetobacter baumannii are Gram-negative bacilli that pose a constant threat to susceptible patients because of increased resistance to multiple antibiotics and persistence in the hospital environment. After genome analysis, we discovered that A. baumannii harbors genes that share homology to an enzymatic pathway that elongates long-chain fatty acids (LCFA) in fungi. Previously, 1,2,4-triazolidine-3-thiones (T-3-Ts) were shown to inhibit hyphae production in fungi, and this same LCFA elongation pathway was implicated as the possible target. Therefore, we investigated if T-3-Ts also have activity against multidrug-resistant A. baumannii. Surprisingly, all of the clinical isolates of A. baumannii that were tested have susceptibility to ECC145 and ECC188 with MIC90 values of 8.0 μg/mL. In contrast, reference strains and clinical isolates of other common nosocomial bacteria that lack the LCFA pathway also lacked susceptibility. Time-kill experiments revealed that both ECC145 and ECC188 have a bacteriostatic effect against A. baumannii. Mass spectrometry analysis suggested that exposure to T-3-Ts resulted in less LCFA production. Supplementation of media with either 0.02% w/v oleic or linoleic acid abrogated the bacteriostatic effect of the compounds, which again implicated LCFA elongation as the target. Our results suggest these molecules could be a promising start to further exploit what appears to be an important aspect of A. baumannii membrane function and integrity.

Authors+Show Affiliations

Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, Maryland 21201, United States.Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.Department of Veterinary Medicine, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.Department of Chemistry, North Carolina State University , Raleigh, North Carolina 27695-8024, United States.Department of Chemistry, North Carolina State University , Raleigh, North Carolina 27695-8024, United States.Department of Chemistry, North Carolina State University , Raleigh, North Carolina 27695-8024, United States.Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, Maryland 21201, United States.Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27764938

Citation

Corey, Brendan W., et al. "1,2,4-Triazolidine-3-thiones Have Specific Activity Against Acinetobacter Baumannii Among Common Nosocomial Pathogens." ACS Infectious Diseases, vol. 3, no. 1, 2017, pp. 62-71.
Corey BW, Thompson MG, Hittle LE, et al. 1,2,4-Triazolidine-3-thiones Have Specific Activity against Acinetobacter baumannii among Common Nosocomial Pathogens. ACS Infect Dis. 2017;3(1):62-71.
Corey, B. W., Thompson, M. G., Hittle, L. E., Jacobs, A. C., Asafo-Adjei, E. A., Huggins, W. M., Melander, R. J., Melander, C., Ernst, R. K., & Zurawski, D. V. (2017). 1,2,4-Triazolidine-3-thiones Have Specific Activity against Acinetobacter baumannii among Common Nosocomial Pathogens. ACS Infectious Diseases, 3(1), 62-71. https://doi.org/10.1021/acsinfecdis.6b00133
Corey BW, et al. 1,2,4-Triazolidine-3-thiones Have Specific Activity Against Acinetobacter Baumannii Among Common Nosocomial Pathogens. ACS Infect Dis. 2017 01 13;3(1):62-71. PubMed PMID: 27764938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 1,2,4-Triazolidine-3-thiones Have Specific Activity against Acinetobacter baumannii among Common Nosocomial Pathogens. AU - Corey,Brendan W, AU - Thompson,Mitchell G, AU - Hittle,Lauren E, AU - Jacobs,Anna C, AU - Asafo-Adjei,Edward A, AU - Huggins,William M, AU - Melander,Roberta J, AU - Melander,Christian, AU - Ernst,Robert K, AU - Zurawski,Daniel V, Y1 - 2016/11/03/ PY - 2016/11/5/pubmed PY - 2018/2/10/medline PY - 2016/11/5/entrez KW - ESKAPE pathogens KW - Gram-negative membrane KW - antibacterial KW - antibiotic KW - fatty acids KW - fungi SP - 62 EP - 71 JF - ACS infectious diseases JO - ACS Infect Dis VL - 3 IS - 1 N2 - Acinetobacter baumannii are Gram-negative bacilli that pose a constant threat to susceptible patients because of increased resistance to multiple antibiotics and persistence in the hospital environment. After genome analysis, we discovered that A. baumannii harbors genes that share homology to an enzymatic pathway that elongates long-chain fatty acids (LCFA) in fungi. Previously, 1,2,4-triazolidine-3-thiones (T-3-Ts) were shown to inhibit hyphae production in fungi, and this same LCFA elongation pathway was implicated as the possible target. Therefore, we investigated if T-3-Ts also have activity against multidrug-resistant A. baumannii. Surprisingly, all of the clinical isolates of A. baumannii that were tested have susceptibility to ECC145 and ECC188 with MIC90 values of 8.0 μg/mL. In contrast, reference strains and clinical isolates of other common nosocomial bacteria that lack the LCFA pathway also lacked susceptibility. Time-kill experiments revealed that both ECC145 and ECC188 have a bacteriostatic effect against A. baumannii. Mass spectrometry analysis suggested that exposure to T-3-Ts resulted in less LCFA production. Supplementation of media with either 0.02% w/v oleic or linoleic acid abrogated the bacteriostatic effect of the compounds, which again implicated LCFA elongation as the target. Our results suggest these molecules could be a promising start to further exploit what appears to be an important aspect of A. baumannii membrane function and integrity. SN - 2373-8227 UR - https://www.unboundmedicine.com/medline/citation/27764938/124_Triazolidine_3_thiones_Have_Specific_Activity_against_Acinetobacter_baumannii_among_Common_Nosocomial_Pathogens_ L2 - https://doi.org/10.1021/acsinfecdis.6b00133 DB - PRIME DP - Unbound Medicine ER -