Evolution of Colistin Resistance in the Klebsiella pneumoniae Complex Follows Multiple Evolutionary Trajectories with Variable Effects on Fitness and Virulence Characteristics.
Janssen. Axel B AB; Doorduijn. Dennis J DJ; Mills. Grant G; Rogers. Malbert R C MRC; Bonten. Marc J M MJM; Rooijakkers. Suzan H M SHM; Willems. Rob J L RJL; Bengoechea. Jose A JA; van Schaik. Willem W
Key Findings
- Colistin resistance in Klebsiella arises through diverse mutations, insertions, deletions, and mobile DNA elements affecting LPS and capsule genes
- Resistant strains showed altered lipid A (hydroxylation, palmitoylation, l‑Ara4N addition) and varied effects on bacterial growth rates
- K. pneumoniae sensu stricto strains that became colistin‑resistant also showed cross‑resistance to the human antimicrobial peptide LL‑37, while K. variicola did not
- Two colistin‑resistant strains were more virulent in a C. elegans survival assay
Practical Outcomes
- The study suggests that overusing colistin can not only create drug‑resistant infections but also diminish the effectiveness of the body’s own antimicrobial peptide LL‑37. For those interested in immune health, it underscores the importance of prudent antibiotic use and that resistance can impact innate immunity, but it doesn’t provide new dosing or supplementation guidance for LL‑37.
Summary
Researchers grew four strains of Klebsiella bacteria with the antibiotic colistin and watched them become resistant. They found the bacteria used many different genetic tricks to survive, and some of the resistant bugs also became less vulnerable to the human immune peptide LL‑37 and even more harmful in a worm model. The findings mainly warn that using colistin can make bacteria tougher against both drugs and our own defenses, but they don’t give new ways to use LL‑37 for health.
Abstract
The increasing prevalence of multidrug-resistant <i>Klebsiella pneumoniae</i> has led to a resurgence in the use of colistin as a last-resort drug. Colistin is a cationic antibiotic that selectively acts on Gram-negative bacteria through electrostatic interactions with anionic phosphate groups of the lipid A moiety of lipopolysaccharides (LPSs). Colistin resistance in <i>K. pneumoniae</i> is mediated through loss of these phosphate groups, their modification by cationic groups, and by the hydroxylation of acyl groups of lipid A. Here, we study the <i>in vitro</i> evolutionary trajectories toward colistin resistance in four clinical <i>K. pneumoniae</i> complex strains and their impact on fitness and virulence characteristics. Through population sequencing during <i>in vitro</i> evolution, we found that colistin resistance develops through a combination of single nucleotide polymorphisms, insertions and deletions, and the integration of insertion sequence elements, affecting genes associated with LPS biosynthesis and modification and capsule structures. Colistin resistance decreased the maximum growth rate of one <i>K. pneumoniae</i><i>sensu stricto</i> strain, but not those of the other three <i>K. pneumoniae</i> complex strains. Colistin-resistant strains had lipid A modified through hydroxylation, palmitoylation, and l-Ara4N addition. <i>K. pneumoniae</i><i>sensu stricto</i> strains exhibited cross-resistance to LL-37, in contrast to the <i>Klebsiella variicola</i> subsp. <i>variicola</i> strain. Virulence, as determined in a <i>Caenorhabditis elegans</i> survival assay, was increased in two colistin-resistant strains. Our study suggests that nosocomial <i>K. pneumoniae</i> complex strains can rapidly develop colistin resistance through diverse evolutionary trajectories upon exposure to colistin. This effectively shortens the life span of this last-resort antibiotic for the treatment of infections with multidrug-resistant <i>Klebsiella</i>.
Study Information
pubmed
2020
2020-12-16T00:00:00.000Z
10.1128/aac.01958-20