Synergy between Colistin and the Signal Peptidase Inhibitor MD3 Is Dependent on the Mechanism of Colistin Resistance in Acinetobacter baumannii

Marta Martínez-Guitián; Juan C Vázquez-Ucha; Joshua Odingo; Tanya Parish; Margarita Poza; Richard D Waite; German Bou; David W Wareham; Alejandro Beceiro

doi:10.1128/AAC.00510-16

Synergy between Colistin and the Signal Peptidase Inhibitor MD3 Is Dependent on the Mechanism of Colistin Resistance in Acinetobacter baumannii

Antimicrob Agents Chemother. 2016 Jun 20;60(7):4375-9. doi: 10.1128/AAC.00510-16. Print 2016 Jul.

Authors

Marta Martínez-Guitián¹, Juan C Vázquez-Ucha¹, Joshua Odingo², Tanya Parish², Margarita Poza¹, Richard D Waite³, German Bou¹, David W Wareham³, Alejandro Beceiro⁴

Affiliations

¹ Servicio de Microbiología-Instituto de Investigación Biomédica (INIBIC), Coruña, Spain.
² TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
³ Antimicrobial Research Group, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
⁴ Servicio de Microbiología-Instituto de Investigación Biomédica (INIBIC), Coruña, Spain [email protected].

Abstract

Synergy between colistin and the signal peptidase inhibitor MD3 was tested against isogenic mutants and clinical pairs of Acinetobacter baumannii isolates. Checkerboard assays and growth curves showed synergy against both colistin-susceptible strains (fractional inhibitory concentration index [FICindex] = 0.13 to 0.24) and colistin-resistant strains with mutations in pmrB and phosphoethanolamine modification of lipid A (FICindex = 0.14 to 0.25) but not against colistin-resistant Δlpx strains with loss of lipopolysaccharide (FICindex = 0.75 to 1). A colistin/MD3 combination would need to be targeted to strains with specific colistin resistance mechanisms.

MeSH terms

Acinetobacter baumannii / drug effects*
Acinetobacter baumannii / metabolism
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / genetics
Colistin / pharmacology*
Drug Resistance, Multiple, Bacterial / genetics
Drug Synergism
Microbial Sensitivity Tests
Protease Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
Bacterial Proteins
Protease Inhibitors
Colistin

Grants and funding

This work was supported by the Spanish National Plans for Scientific Research, Development and Technological Innovation 2008-2011 and 2013-2016 and funded by the ISCIII-General Subdirection of Assessment and Promotion of the Research European Regional Development Fund (ERDF) “A way of making Europe” and also by the Spanish Network for Research in Infectious Diseases (REIPI RD12/0015).