Determination of Mutational Timing of Colistin-Resistance Genes through Klebsiella pneumoniae Evolution

Abstract

The emergence and dissemination of carbapenem-resistant Klebsiella pneumoniae (KP), one of the carbapenem-resistant Enterobacteriaceae (CRE), is now an emerging cause of antibiotic-resistant nosocomial infections associated with high rates of morbidity and mortality. Colistin, or polymyxin E, is a last-resort peptide antibiotic used to treat multidrug-resistant (MDR) Gram-negative bacterial infections including KP. Unfortunately, resistance to colistin is rising with increasing use in the clinical setting. Although clinical evidence links certain mutations to colistin resistance (COL-R) in KP, the origination and association of the mutations remain unclear. We hypothesize that the timing of COL-R mutations influences the development and progression of KP resistance to colistin. We performed planktonic and biofilm in vitro experimental evolutions of KP strain ATCC 43816 under increasing colistin concentrations to characterize the temporal regulation of critical COL-R mutations throughout COL-R progression. The resistance generation and mutation profiles of independently evolved bacterial populations with different lifestyles were compared. Genes with various functions theorize the timeline in which key mutations are generated and their roles in the progression of COL-R. Our results aim to advance the research and development of effective therapeutics to treat MDR bacterial infection as the dissemination of CRE continues to be a severe public health threat.

Comparative Genomic Analysis Reveals the Emergence of ST-231 and ST-395 Klebsiella pneumoniae Strains Associated with the High Transmissibility of blaKPC Plasmids

“…However, the detected SNPs in this study have not been described before, and therefore, a further expression analysis by real-time PCR is needed to show their role along with the truncated mgrB gene in colistin resistance. Moreover, colistin resistance might occur due to other resistance mechanisms, such as capsule overproduction, which causes a reduction in the interaction between colistin and its target site at K. pneumoniae (LPS) [88,92]. Furthermore, all isolates in this study carried K. pneumoniae efflux pumps (Kpn E, F, G, H), which might contribute to colistin resistance.…”

Lung SPLUNC1 Peptide Derivatives in the Lipid Membrane Headgroup Kill Gram-Negative Planktonic and Biofilm Bacteria

“…The increasing clinical use of colistin has led to colistin resistance in G(−) bacteria . The pathway to colistin resistance in Klebsiella pneumoniae primarily involves Lipid A modification, and the timing of the COL-R mutations may be key to understanding this resistance . The A4S derivatives differ in length, charge, hydrophobic moment, and hydrophobicity.…”

“… 16 The pathway to colistin resistance in Klebsiella pneumoniae primarily involves Lipid A modification, 17 and the timing of the COL-R mutations may be key to understanding this resistance. 18 The A4S derivatives differ in length, charge, hydrophobic moment, and hydrophobicity. In order to understand the underlying mechanisms of the derivative peptides, we have carried out three biophysical techniques: circular dichroism (CD), X-ray diffuse scattering (XDS), and neutron reflectivity (NR), to probe the secondary structure and interactions between the A4S derivatives and LMMs of Gram-negative (G(−)) inner membranes.…”

The Editorial Position on ‘Recent Advances in Multifunctional Antimicrobial Peptides as Preclinical Therapeutic Studies and Clinical Future Applications’

“…They demonstrated the importance of mutation timing in the progression of the Klebsiella pneumoniae Colistin-resistant strain, identifying a time-specific mutation of Colistin-resistant genes during this pathogen evolution. In particular, the authors observed the onset of an early resistance with mutations relevant to capsule production, cell membrane integrity, and energy metabolism in response to Colistin treatment, followed by mutations influencing LPS structure, strongly impacting Colistin-resistant progression [19].…”