Acquisition of Colistin Resistance Links Cell Membrane Thickness Alteration with a Point Mutation in the lpxD Gene in Acinetobacter baumannii

Abstract

Acinetobacter baumannii is one of the most common causes of nosocomial infections in intensive care units. Its ability to acquire diverse mechanisms of resistance limits the therapeutic choices for its treatment. This especially concerns colistin, which has been reused recently as a last-resort drug against A. baumannii. Here, we explored the impact of gaining colistin resistance on the susceptibility of A. baumannii to other antibiotics and linked colistin resistance acquisition to a gene mutation in A. baumannii. The susceptibility of 95 A. baumannii isolates revealed that 89 isolates were multi-drug resistance (MDR), and nine isolates were resistant to colistin. Subsequently, three isolates, i.e., MS48, MS50, and MS64, exhibited different resistance patterns when colistin resistance was induced and gained resistance to almost all tested antibiotics. Upon TEM examination, morphological alterations were reported for all induced isolates and a colistin-resistant clinical isolate (MS34Col-R) compared to the parental sensitive strains. Finally, genetic alterations in PmrB and LpxACD were assessed, and a point mutation in LpxD was identified in the MS64Col-R and MS34Col-R mutants, corresponding to Lys117Glu substitution in the lipid-binding domain. Our findings shed light on the implications of using colistin in the treatment of A. baumannii, especially at sub-minimum inhibitory concentrations concentrations, since cross-resistance to other classes of antibiotics may emerge, beside the rapid acquisition of resistance against colistin itself due to distinct genetic events.

Molecular characterization of lpxACD and pmrA/B two-component regulatory system in the colistin resistance Acinetobacter baumannii clinical isolates

“…Whole-genome sequencing analysis of the Col-R A. baumannii strains revealed that, the main causes of the resistance to colistin were mutations in the pmrA-pmrB genes, including pmrAP102 → R, pmrBP233 → S, pmrBT235 → N, and the novel alleles pmrAI13 → M and pmrBQ270 → P (Sun et al, 2020). Similar to our work, Saleh et al (2020) reported that two amino acid substitutions (A95 → T and P157 → R) in the transmembrane domains of PmrB cause low-level resistance to colistin.…”

Regulation of overexpressed efflux pump encoding genes by cinnamon oil and trimethoprim to abolish carbapenem-resistant Acinetobacter baumannii clinical strains

“…Although colistin sulfate is the last resort for the treatment of A. baumannii infections, colistin resistance has been reported in 60% of strains in our study, and this higher rate is recently documented previously [ 37 , 40 , 41 ]. Correspondingly, some studies revealed that colistin retains its effectiveness against A. baumannii in Egypt (4.5%, and 7.4%) by El-Masry and Masry and Elsherbeny et al, respectively [ 42 , 43 ].…”

Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria

“…The mutations in lipid A biosynthesis genes, lpxA, lpxC , and lpxD , cause total loss of LPS production halting colistin binding to membrane and hence colistin resistance. There are mutations in the first three genes of the LPS production and therefore complete loss of the LPS layer ( 19 , 192 ).…”