Transition of colistin dependence into colistin resistance in Acinetobacter baumannii

Abstract

We recently demonstrated a high rate of colistin dependence in Acinetobacter baumannii isolates exposed to colistin in vitro. In the present study, we obtained a colistin-resistant (H08-391R) and colistin-dependent mutant (H08-391D) from a colistin-susceptible parental strain (H08-391). We found that the colistin-dependent mutant converted into a stable colistin-resistant mutant (H08-391D-R) in vitro after four serial passages without colistin. H08-391D and H08-391D-R were both found to harbor defective lipid A, as indicated by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry analysis. Additionally, both contained an ISAba1 insertion in lpxC, which encodes a lipid A biosynthetic enzyme. Further, membrane potential measurements using the fluorescent dye 3,3′-diethyloxacarbocyanine iodide (DiOC2[3]) showed that the membrane potential of H08-391D and H08-391D-R was significantly decreased as compared to that of the parental strain, H08-391. Moreover, these mutant strains exhibited increased susceptibilities to antibiotics other than colistin, which may be attributed to their outer membrane fragility. Such phenomena were identified in other A. baumannii strains (H06-855 and its derivatives). Taken together, our study reveals that the colistin-dependent phenotype is a transient phenotype that allows A. baumannii to survive under colistin pressure, and can transition to the extremely resistant phenotype, even in an antibiotic-free environment.

Interplay of Klebsiella pneumoniae fabZ and lpxC Mutations Leads to LpxC Inhibitor-Dependent Growth Resulting from Loss of Membrane Homeostasis

“…Although rare, cases where bacteria have developed a dependence on an antibacterial compound for growth have been described, for example with streptomycin, colistin, and vancomycin ( 8 , 50 – 55 ). Here we describe the isolation of K. pneumoniae mutants whose growth requires the inhibition of LpxC.…”

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

“…Thus, the development of colistin-dependent mutants may have clinical significance, and it should be investigated. A recent study showed that the colistin-dependent phenotype may arise from the loss of LPS or defects in its structure, resulting from the disruption of LpxC [83]. In that study, transition of colistin dependence into colistin resistance was also demonstrated in the absence of antibiotic selection pressure [83].…”

<p>Molecular Characterization of Carbapenem/Colistin-Resistant <em>Acinetobacter baumannii</em> Clinical Isolates from Egypt by Whole-Genome Sequencing</p>

“…However, resistance towards colistin among A. baumannii has become a serious problem as there are no alternative available therapeutic options. 6 There are now reports from different regions of the world of pan-drug-resistant (PDR) A. baumannii. 7 The primary resistance mechanism is mediated through the modification of the lipid A moiety of lipopolysaccharide (LPS) through the addition of phosphoethanolamine (PEtN) through overexpression and/or mutations in the two-component regulatory system PmrA and PmrB.…”