Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in Escherichia coli by Affecting pmrAB System
Received 1 May 2020
Accepted for publication 16 June 2020
Published 10 July 2020 Volume 2020:13 Pages 2205—2222
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Suresh Antony
Dipak Kathayat,1 Linto Antony,2 Loic Deblais,1 Yosra A Helmy,1 Joy Scaria,2 Gireesh Rajashekara1
1Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH 44691, USA; 2Animal Disease Research and Diagnostic Laboratory, Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA
Correspondence: Gireesh Rajashekara 1680 Madison Avenue, Wooster, OH 44691, USA
Tel +1 330-263-3745
Fax +1 330-263-3744
Background: Colistin is one of the last-resort antibiotics to treat multi-drug resistant (MDR) Gram-negative bacterial infections in humans. Further, colistin has been also used to prevent and treat Enterobacteriaceae infections in food animals. However, chromosomal mutations and mobile colistin resistance (mcr) genes, which confer resistance to colistin, have been detected in bacterial isolates from food animals and humans worldwide; thus, limiting the use of colistin. Therefore, strategies that could aid in ameliorating colistin resistance are critically needed.
Objective: Investigate the adjuvant potential of novel small molecules (SMs) on colistin.
Materials and Methods: Previously, we identified 11 membrane-affecting SMs with bactericidal activity against avian pathogenic Escherichia coli (APEC). Here, we investigated the potentiation effect of those SMs on colistin using checkerboard assays and wax moth (Galleria mellonella) larval model. The impact of the SM combination on colistin resistance evolution was also investigated by analyzing whole genome sequences of APEC isolates passaged with colistin alone or in combination with SMs followed by quantitating pmrCAB and pmrH expression in those isolates.
Results: The SM combination synergistically reduced the minimum bactericidal concentration of colistin by at least 10-fold. In larvae, the SM combination increased the efficacy of colistin by two-fold with enhanced (> 50%) survival and reduced (> 4 logs) APEC load. Further, the SM combination decreased the frequency (5/6 to 1/6) of colistin resistance evolution and downregulated the pmrCAB and pmrH expression. Previously unknown mutations in pmrB (L14Q, T92P) and pmrA (A80V), which were predicted deleterious, were identified in the colistin-resistant (ColR) APEC isolates when passaged with colistin alone but not in combination with SMs. Our study also identified mutations in hypothetical and several phage-related proteins in ColR APEC isolates in concurrent with pmrAB mutations.
Conclusion: Our study identified two SMs (SM2 and SM3) that potentiated the colistin activity and attenuated the development of colistin resistance in APEC. These SMs can be developed as anti-evolution drugs that can slow down colistin resistance development.
Keywords: colistin, small molecules, pmrCAB, pmrH, resistance, anti-evolution drug
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]