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

Albert B. Jeon, Andrés Obregón-Henao, David F. Ackart, Brendan K. Podell, Juan M. Belardinelli, Mary Jackson, Tuan V. Nguyen, Meghan S. Blackledge, Roberta J. Melander, Christian Melander, Benjamin K. Johnson, Robert B. Abramovitch, Randall J. Basaraba

Research output: Contribution to journalArticle

Abstract

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 ß-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 ß-lactam antibiotics against M. tuberculosis. Active 2-AI compounds significantly reduced the minimal inhibitory and bactericidal concentrations of ß-lactams by increasing M. tuberculosis cell envelope permeability and decreasing protein secretion including ß-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 ß-lactams by a mechanism that is distinct from specific inhibitors of ß-lactamase activity and therefore may have value as an adjunctive anti-TB treatment.

Original languageEnglish (US)
Article numbere0180925
JournalPLoS ONE
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2017

Profile

Mycobacterium tuberculosis
Lactams
Permeability
lactams
Anti-Bacterial Agents
permeability
antibiotics
cells
Molecules
antimicrobial agents
Common Bile Duct Diseases
Carnitine Acyltransferases
Bronchiolo-Alveolar Adenocarcinoma
Addison Disease
Blood Flow Velocity
Strabismus
Mastication
Castration
Biosynthesis
Mycolic Acids

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Jeon, A. B., Obregón-Henao, A., Ackart, D. F., Podell, B. K., Belardinelli, J. M., Jackson, M., ... Basaraba, R. J. (2017). 2-Aminoimidazoles potentiate ß-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing ß-lactamase secretion and increasing cell envelope permeability. PLoS ONE, 12(7), [e0180925]. DOI: 10.1371/journal.pone.0180925

2-Aminoimidazoles potentiate ß-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing ß-lactamase secretion and increasing cell envelope permeability. / Jeon, Albert B.; Obregón-Henao, Andrés; Ackart, David F.; Podell, Brendan K.; Belardinelli, Juan M.; Jackson, Mary; Nguyen, Tuan V.; Blackledge, Meghan S.; Melander, Roberta J.; Melander, Christian; Johnson, Benjamin K.; Abramovitch, Robert B.; Basaraba, Randall J.

In: PLoS ONE, Vol. 12, No. 7, e0180925, 01.07.2017.

Research output: Contribution to journalArticle

Jeon, AB, Obregón-Henao, A, Ackart, DF, Podell, BK, Belardinelli, JM, Jackson, M, Nguyen, TV, Blackledge, MS, Melander, RJ, Melander, C, Johnson, BK, Abramovitch, RB & Basaraba, RJ 2017, '2-Aminoimidazoles potentiate ß-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing ß-lactamase secretion and increasing cell envelope permeability' PLoS ONE, vol 12, no. 7, e0180925. DOI: 10.1371/journal.pone.0180925

Jeon, Albert B.; Obregón-Henao, Andrés; Ackart, David F.; Podell, Brendan K.; Belardinelli, Juan M.; Jackson, Mary; Nguyen, Tuan V.; Blackledge, Meghan S.; Melander, Roberta J.; Melander, Christian; Johnson, Benjamin K.; Abramovitch, Robert B.; Basaraba, Randall J. / 2-Aminoimidazoles potentiate ß-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing ß-lactamase secretion and increasing cell envelope permeability.

In: PLoS ONE, Vol. 12, No. 7, e0180925, 01.07.2017.

Research output: Contribution to journalArticle

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