TY - JOUR

T1 - Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin, and sodium deoxycholate triple combination in escherichia coli

AU - Olivera, Catrina

AU - Cox, Murray P.

AU - Rowlands, Gareth J.

AU - Rakonjac, Jasna

N1 - Funding Information: This work was supported by a Massey University-MBIE PSAF II grant MU001985 and a generous donation by Anne and Bryce Carmine. We are indebted to Bryce and Anne Carmine for their generous donation that made this work possible. C.O. was supported by a Massey University PhD Scholarship. Funding from the College of Sciences MURF (covering publication fees) and School of Fundamental Sciences is gratefully acknowledged. Publisher Copyright: © 2021 American Society for Microbiology. All rights reserved.

PY - 2021

Y1 - 2021

N2 - Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug- resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms.

AB - Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug- resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms.

KW - Antibiotic resistance

KW - Antibiotic synergy

KW - Bile salts

KW - Enterobacteriaceae

KW - Escherichia coli

KW - Furazolidone

KW - Gram-negative bacteria

KW - Nitrofuran

KW - Sodium deoxycholate

KW - Vancomycin

U2 - 10.1128/mSphere.00627-21

DO - 10.1128/mSphere.00627-21

M3 - Journal article

C2 - 34494879

AN - SCOPUS:85118842027

VL - 6

JO - mSphere

JF - mSphere

SN - 2379-5042

IS - 5

M1 - e00627-21

ER -