2-aminoimidazoles potentiate β-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing β-lactamase secretion and increasing cell envelope permeability

被引:16
作者
Jeon, Albert B. [1 ]
Obregon-Henao, Andres [1 ]
Ackart, David F. [1 ]
Podell, Brendan K. [1 ]
Belardinelli, Juan M. [1 ]
Jackson, Mary [1 ]
Nguyen, Tuan V. [2 ]
Blackledge, Meghan S. [3 ]
Melander, Roberta J. [2 ]
Melander, Christian [2 ]
Johnson, Benjamin K. [4 ]
Abramovitch, Robert B. [4 ]
Basaraba, Randall J. [1 ]
机构
[1] Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA
[2] North Carolina State Univ, Dept Chem, Raleigh, NC USA
[3] High Point Univ, Dept Chem, High Point, NC USA
[4] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA
来源
PLOS ONE | 2017年 / 12卷 / 07期
关键词
DIFFERENTIAL EXPRESSION ANALYSIS; OUTER-MEMBRANE PERMEABILITY; 2-COMPONENT SYSTEM; TREATMENT REGIMENS; ETHIDIUM-BROMIDE; DRUG-RESISTANCE; LIPID-BILAYER; SIGMA-FACTORS; VIRULENCE; WALL;
D O I
10.1371/journal.pone.0180925
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
There is an urgent need to develop new drug treatment strategies to control the global spread of drug-sensitive and multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). The beta-lactam class of antibiotics is among the safest and most widely prescribed antibiotics, but they are not effective against M. tuberculosis due to intrinsic resistance. This study shows that 2-aminoimidazole (2-AI)-based small molecules potentiate beta-lactam antibiotics against M. tuberculosis. Active 2-AI compounds significantly reduced the minimal inhibitory and bactericidal concentrations of beta-lactams by increasing M. tuberculosis cell envelope permeability and decreasing protein secretion including beta-lactamase. Metabolic labeling and transcriptional profiling experiments revealed that 2-AI compounds impair mycolic acid biosynthesis, export and linkage to the mycobacterial envelope, counteracting an important defense mechanism reducing permeability to external agents. Additionally, other important constituents of the M. tuberculosis outer membrane including sulfolipid-1 and polyacyltrehalose were also less abundant in 2-AI treated bacilli. As a consequence of 2-AI treatment, M. tuberculosis displayed increased sensitivity to SDS, increased permeability to nucleic acid staining dyes, and rapid binding of cell wall targeting antibiotics. Transcriptional profiling analysis further confirmed that 2-AI induces transcriptional regulators associated with cell envelope stress. 2-AI based small molecules potentiate the antimicrobial activity of beta-lactams by a mechanism that is distinct from specific inhibitors of beta-lactamase activity and therefore may have value as an adjunctive anti-TB treatment.
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页数:29
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