A novel mutation in pmrB mediates colistin resistance during therapy of Acinetobacter baumannii

Dahdouh, Elias; Gómez-Gil, Rosa; Sanz, Sonia; González‐Zorn, Bruno; Daoud, Ziad; Mingorance, Jesús; Suárez, Mónica

doi:10.1016/j.ijantimicag.2017.01.031

Cited by 23 publications

(19 citation statements)

References 33 publications

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“…Several studies have described colistin-resistant A. baumannii isolates with reduced fitness and impaired virulence (32,33,44,45), while other studies are in agreement with our observation of unchanged fitness or growth characteristics (34)(35). Retention of fitness and virulence in colistin-resistant isolates has been attributed to the mechanism of resistance.…”

Section: Discussionsupporting

confidence: 91%

“…In the present study, we have investigated colistin resistance in four isogenic isolate pairs of A. baumannii, which gives us the ability to analyze the resistance mechanisms in very similar genetic backgrounds and exclude typical genetic variations seen in epidemiologically unrelated strains. Similar approaches have been conducted by, e.g., Dahdouh et al, Durante-Mangoni et al, and Beceiro et al, the latter reporting pmrB mutations, increased pmrC expression, and lipid A modification in colistin-resistant A. baumannii isolates (24,34,35). Many different amino acid substitutions or short amino acid deletions have been described in PmrB, both in clinical and in laboratory-derived A. baumannii isolates (14).…”

Section: Discussionsupporting

confidence: 59%

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Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo

Gerson

Betts

Lucaßen

et al. 2019

Antimicrob Agents Chemother

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Colistin resistance in Acinetobacter baumannii is of great concern and is a threat to human health. In this study, we investigate the mechanisms of colistin resistance in four isogenic pairs of A. baumannii isolates displaying an increase in colistin MICs. A mutation in pmrB was detected in each colistin-resistant isolate, three of which were novel (A28V, I232T, and ΔL9-G12). Increased expression of pmrC was shown by semi-quantitative reverse transcription-PCR (qRT-PCR) for three colistin-resistant isolates, and the addition of phosphoethanolamine (PEtN) to lipid A by PmrC was revealed by mass spectrometry. Interestingly, PEtN addition was also observed in some colistin-susceptible isolates, indicating that this resistance mechanism might be strain specific and that other factors could contribute to colistin resistance. Furthermore, the introduction of pmrAB carrying the short amino acid deletion ΔL9-G12 into a pmrAB knockout strain resulted in increased pmrC expression and lipid A modification, but colistin MICs remained unchanged, further supporting the strain specificity of this colistin resistance mechanism. Of note, a mutation in the pmrC homologue eptA and a point mutation in ISAba1 upstream of eptA were associated with colistin resistance and increased eptA expression, which is a hitherto undescribed resistance mechanism. Moreover, no cost of fitness was observed for colistin-resistant isolates, while the virulence of these isolates was increased in a Galleria mellonella infection model. Although the mutations in pmrB were associated with colistin resistance, PEtN addition appears not to be the sole factor leading to colistin resistance, indicating that the mechanism of colistin resistance is far more complex than previously suspected and is potentially strain specific.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 59%

Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo

Gerson

Betts

Lucaßen

et al. 2019

Antimicrob Agents Chemother

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“…These LPS alterations decrease the net negative charge, preventing the binding of the cationic polymyxin molecules to the bacterial surface ( Jeannot et al, 2017 ; Poirel et al, 2017 ). PmrAB is a two-component regulatory system that regulates the expression of the genes involved in LPS modification; some mutations in pmrAB resulted in polymyxin resistance due to constitutive upregulation of the LPS modification pathway ( Arroyo et al, 2011 ; Park et al, 2011 ; Lim et al, 2015 ; Dahdouh et al, 2017 ). Investigations into the polymyxin-resistant A. baumannii isolates from HSNZ in 2011 indicated a P102H mutation in the pmrA gene in all resistant isolates and several point mutations in the lpxC, lpxD and lpsB genes involved in LPS biosynthesis ( Lean et al, 2014 ).…”

Section: Resistance Mechanismsmentioning

confidence: 99%

Acinetobacter spp. Infections in Malaysia: A Review of Antimicrobial Resistance Trends, Mechanisms and Epidemiology

et al. 2017

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Acinetobacter spp. are important nosocomial pathogens, in particular the Acinetobacter baumannii-calcoaceticus complex, which have become a global public health threat due to increasing resistance to carbapenems and almost all other antimicrobial compounds. High rates of resistance have been reported among countries in Southeast Asia, including Malaysia. In this review, we examine the antimicrobial resistance profiles of Acinetobacter spp. hospital isolates from Malaysia over a period of nearly three decades (1987–2016) with data obtained from various peer-reviewed publications as well as the Malaysian National Surveillance on Antibiotic Resistance (NSAR). NSAR data indicated that for most antimicrobial compounds, including carbapenems, the peak resistance rates were reached around 2008–2009 and thereafter, rates have remained fairly constant (e.g., 50–60% for carbapenems). Individual reports from various hospitals in Peninsular Malaysia do not always reflect the nationwide resistance rates and often showed higher rates of resistance. We also reviewed the epidemiology and mechanisms of resistance that have been investigated in Malaysian Acinetobacter spp. isolates, particularly carbapenem resistance and found that blaOXA-23 is the most prevalent acquired carbapenemase-encoding gene. From the very few published reports and whole genome sequences that are available, most of the Acinetobacter spp. isolates from Malaysia belonged to the Global Clone 2 (GC2) CC92 group with ST195 being the predominant sequence type. The quality of data and analysis in the national surveillance reports could be improved and more molecular epidemiology and genomics studies need to be carried out for further in-depth understanding of Malaysian Acinetobacter spp. isolates.

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“…Colistin, a cationic peptide that disrupts Outer membrane(OM), was recognized as a last-resort treatment. Unfortunately, the abuse of colistin, as a consequence of prolonged exposure, is leading to colistin resistance, which is reported periodically [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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A novel mutation in pmrB mediates colistin resistance during therapy of Acinetobacter baumannii

Cited by 23 publications

References 33 publications

Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo

Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo

Acinetobacter spp. Infections in Malaysia: A Review of Antimicrobial Resistance Trends, Mechanisms and Epidemiology

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

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