Functional and population-genomic dissection of rifabutin response in carbapenem-resistant Acinetobacter baumannii

Le résumé fourni par la source

Rifamycins, and rifabutin (RFB) in particular, have re-emerged as candidate agents against carbapenem-resistant Acinetobacter baumannii (CRAB), with previous data proposing the siderophore receptor FhuE as the principal route of RFB uptake. Here we combined targeted mutant screening, killing-dynamics assays, scanning electron microscopy and population-scale comparative genomics to test whether this single-receptor model captures the determinants of RFB response. Among the candidate loci examined, only disruption of ABUW_0143 produced a reproducible increase in RFB MIC and impaired RFB-mediated killing under the conditions tested. ABUW_0143 disruption was also associated with a paradoxical, non-monotonic concentration-response, in which a lower RFB concentration (0.25 µg/mL) was more bactericidal than higher concentrations (1-8 µg/mL), consistent with an Eagle-like effect. In the high-MIC strain AMA3, prolonged RFB exposure at the MIC selected small-colony-variant-like survivors without an accompanying MIC increase, and scanning electron microscopy showed rifabutin-associated changes in cell clustering and dispersion rather than gross single-cell morphological damage. Checkerboard assays further indicated that RFB-meropenem combinations, but not RFB-sulbactam combinations, improved activity in several reduced-susceptibility backgrounds. At the population scale, analysis of 49,834 A. baumannii genomes showed that FhuE tracked more closely with sequence type (ST) than ABUW_0143 (adjusted mutual information 0.839 versus 0.730), and that the strong global ABUW_0143-FhuE co-occurrence (Cramer's V = 0.712) collapsed toward the ST-stratified permutation null (delta = 0.027), indicating that this association is largely a byproduct of clonal population structure; only 3 of 701 ABUW_0143-FhuE allele pairs retained evidence of an ST-independent association. Together, these functional and genomic data support ABUW_0143 as an additional, FhuE-independent determinant of RFB susceptibility and killing dynamics in A. baumannii.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.