Increasing the tigecycline concentration to 0.5 μg/mL resulted in a marked 4.7-log10 CFU reduction for AB1026 at 8 h, which was followed by regrowth, whereas a smaller reduction was observed for the wild-type strain. baeR reconstitution did not fully restore the ability of AB1026 to resist 0.5 μg/mL tigecycline. AB1028 had a slight, though not significant, CFU reduction compared Nec-1s mouse to the wild-type strain in the presence of 0.25 or 0.5 μg/mL tigecycline. Viable counts represented by CFUs were determined at time 0 and at 4, 8, 12, and 16 h after inoculation. A
time-kill curve was constructed for each strain. The results are displayed as the means ± SD from three independent experiments. *, P < 0.05. Discussion Previous studies that investigated the regulation of AdeABC efflux pumps in A. baumannii primarily focused on the AdeRS TCS, which is located upstream of the adeABC operon and is transcribed in the opposite direction [15]. Several point mutations in adeR or adeS have been proposed as the major cause of AdeABC efflux pump overexpression, SU5402 mouse including a threonine-to-methionine substitution at position 153 [15], a glycine-to-aspartate mutation at position 30 [24], an alanine-to-valine substitution at position 94 of AdeS [25], or a proline-to-leucine substitution at position 116 of AdeR [15]. However, the effect of AdeR or AdeS mutations
on the expression of AdeABC is not always consistent. Different tigecycline MICs were observed in two transformed strains with the same mutations
in the DNA-binding Astemizole domain of the AdeR protein [16]. adeABC-overexpressing mutants that did not carry any mutations in adeRS compared with their isogenic parents were also reported [7, 25]. Another mechanism leading to the overexpression of AdeABC involves the transposition of an ISAba1 copy into adeS[15], which stimulates AdeR to interact with and activate the adeABC promoter [16]. In contrast to the results of the above-mentioned studies of AdeRS, four imipenem-resistant A. baumannii strains carrying adeB but lacking adeRS were identified by Hou et al. [26], suggesting that another regulatory mechanism may be involved. Henry et al. reported that BaeSR was associated with the increased expression of the multidrug resistance-associated efflux pump genes macAB-tolC and adeIJK in their transcriptional analysis of lipopolysaccharide-deficient A. baumannii 19606R [27]. Therefore, the role of BaeSR in the expression of the AdeABC efflux pump deserves investigation. Our data demonstrate that BaeSR influences the tigecycline susceptibility of A. baumannii ATCC 17978 Sotrastaurin nmr through its positive regulation of the transcription of transporter genes adeA and adeB. This result supported the possibility that other TCSs aside from AdeRS may be involved in the regulation of the AdeABC efflux pump in A. baumannii. Most A.
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