Role of AxyABM overexpression in acquired resistance in Achromobacter xylosoxidans

• Published in: Journal of antimicrobial chemotherapy Vol. 77; no. 4; pp. 926 - 929
• Main Authors: Magallon, Arnaud, Amoureux, Lucie, Garrigos, Thomas, Sonois, Marine, Varin, Véronique, Neuwirth, Catherine, Bador, Julien
• Format: Journal Article
• Language: English
• Published: England 31.03.2022
• Subjects: Achromobacter - genetics; Achromobacter denitrificans - genetics; Anti-Bacterial Agents - pharmacology; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkab479

Acquired antimicrobial resistance among Achromobacter isolates from cystic fibrosis (CF) patients is frequent. Data concerning the mechanisms involved are scarce. The role of the AxyXY-OprZ and AxyEF-OprN Resistance Nodulation Division (RND) efflux systems has been demonstrated, but not that of AxyABM. To explore the role of efflux systems in the acquired multiresistance observed in a one-step mutant selected after ofloxacin exposure. The in vitro resistant mutant NCF-39-Bo2 and its parental strain NCF-39 (MICs of meropenem of 8 and 0.19 mg/L, of ceftazidime of 12 and 3 mg/L, of cefiderocol of 0.094 and 0.032 mg/L and of ciprofloxacin of 8 and 1.5 mg/L, respectively) were investigated by RNA-seq and WGS. Gene inactivation and reverse transcription quantitative PCR (RT-qPCR) were used to explore the role of the efflux systems of interest. RNA-seq showed that the AxyABM efflux system was overproduced (about 40-fold) in the in vitro mutant NCF-39-Bo2 versus its parental strain NCF-39. A substitution in AxyR, the putative regulator of AxyABM, was detected in NCF-39-Bo2. Gene inactivation of axyB (encoding the transporter component) in NCF-39-Bo2 led to a decrease in MICs of ciprofloxacin (5-fold), meropenem (64-fold), ceftazidime (12-fold) and cefiderocol (24-fold). Inactivation of axyB in the clinical isolate AXX-H2 harbouring a phenotype of resistance close to that of NCF-39-Bo2 enhanced the activity of the same molecules, especially meropenem. AxyABM overproduction is involved in acquired resistance of Achromobacter to ciprofloxacin, meropenem and ceftazidime, antibiotics widely used in CF patients, and increases the MIC of the new promising antibiotic cefiderocol.