Abstract
The carbapenem-resistant Acinetobacter calcoaceticus-baumannii (ACB) complex has become an urgent threat worldwide. Here, we determined antibiotic combinations and the feasible synergistic mechanisms against three couples of ACB (A. baumannii (AB250 and A10), A. pittii (AP1 and AP23), and A. nosocomialis (AN4 and AN12)). Imipenem with fosfomycin, the most effective in the time-killing assay, exhibited synergism to all strains except AB250. MurA, a fosfomycin target encoding the first enzyme in the de novo cell wall synthesis, was observed with the wild-type form in all isolates. Fosfomycin did not upregulate murA, indicating the MurA-independent pathway (cell wall recycling) presenting in all strains. Fosfomycin more upregulated the recycling route in synergistic strain (A10) than non-synergistic strain (AB250). Imipenem in the combination dramatically downregulated the recycling route in A10 but not in AB250, demonstrating the additional effect of imipenem on the recycling route, possibly resulting in synergism by the agitation of cell wall metabolism. Moreover, heteroresistance to imipenem was observed in only AB250. Our results indicate that unexpected activity of imipenem on the active cell wall recycling concurrently with the presence of heteroresistance subpopulation to imipenem may lead to the synergism of imipenem and fosfomycin against the ACB isolates.
Highlights
The carbapenem-resistant Acinetobacter calcoaceticus-baumannii (ACB) complex has become an urgent threat worldwide
The two couples of A. baumannii (AB250 and A10) and A. pittii (AP1 and AP23), unique clones emerging in our hospital, and a pair of A. nosocomialis (AN4 and AN12) were included in this study
A couple of A. baumannii and A. pittii in our study belonged to new sequence type (ST) submitted to the PubMLST22, indicating unique clones emerging in our hospital
Summary
The carbapenem-resistant Acinetobacter calcoaceticus-baumannii (ACB) complex has become an urgent threat worldwide. Our results indicate that unexpected activity of imipenem on the active cell wall recycling concurrently with the presence of heteroresistance subpopulation to imipenem may lead to the synergism of imipenem and fosfomycin against the ACB isolates. P. aeruginosa and A. baumannii are intrinsically resistant to fosfomycin by cell wall recycling pathway[14,15]. The C1 hydroxyl group of MurNAc is phosphorylated by MurNAc kinase (AmgK), yielding MurNAc-α-1P that is converted to cell wall precursor, UDP-MurNAc, by N-acetylmuramate α-1-P uridylyltransferase (MurU). We previously reported that imipenem in combination with fosfomycin was effective against carbapenem-resistant A. baumannii[16]. Mutation and expression of MurA, overexpression of efflux pump, and expression of cell wall recycling enzymes were evaluated. The heteroresistance characteristics were identified by using a population analysis profile (PAP) assay
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