Biological Cost of Different Mechanisms of Colistin Resistance and Their Impact on Virulence in Acinetobacter baumannii

Abstract

ABSTRACTTwo mechanisms of resistance to colistin have been described inAcinetobacter baumannii. One involves complete loss of lipopolysaccharide (LPS), resulting from mutations inlpxA,lpxC, orlpxD, and the second is associated with phosphoethanolamine addition to LPS, mediated through mutations inpmrAB. In order to assess the clinical impacts of both resistance mechanisms,A. baumanniiATCC 19606 and its isogenic derivatives, AL1851 ΔlpxA, AL1852 ΔlpxD, AL1842 ΔlpxC, and ATCC 19606pmrB, were analyzed forin vitrogrowth rate,in vitroandin vivocompetitive growth, infection of A549 respiratory alveolar epithelial cells, virulence in theCaenorhabditis elegansmodel, and virulence in a systemic mouse infection model. Thein vitrogrowth rate of thelpxmutants was clearly diminished; furthermore,in vitroandin vivocompetitive-growth experiments revealed a reduction in fitness for both mutant types. Infection of A549 cells with ATCC 19606 or thepmrBmutant resulted in greater loss of viability than withlpxmutants. Finally, thelpxmutants were highly attenuated in both theC. elegansand mouse infection models, while thepmrBmutant was attenuated only in theC. elegansmodel. In summary, while colistin resistance inA. baumanniiconfers a clear selective advantage in the presence of colistin treatment, it causes a noticeable cost in terms of overall fitness and virulence, with a more striking reduction associated with LPS loss than with phosphoethanolamine addition. Therefore, we hypothesize that colistin resistance mediated by changes inpmrABwill be more likely to arise in clinical settings in patients treated with colistin.