Adaptive antibiotic resistance is a newly described phenomenon by which Acinetobacter baumannii induces efflux pump activity in response to host-associated environmental cues that may, in part, account for
antibiotic treatment failures against clinically defined susceptible strains. To that end, during adaptation to growth in human serum, the organism induces approximately 22 putative efflux-associated genes and displays efflux-mediated
minocycline tolerance at
antibiotic concentrations corresponding to patient serum levels. Here, we show that in addition to
minocycline, growth in human serum elicits A. baumannii efflux-mediated tolerance to the
antibiotics ciprofloxacin,
meropenem,
tetracycline, and
tigecycline. Moreover, using a whole-cell high-throughput screen and secondary assays, we identified novel serum-associated
antibiotic efflux inhibitors that potentiated the activities of
antibiotics toward serum-grown A. baumannii. Two compounds,
Acinetobacter baumannii efflux pump inhibitor 1 (
ABEPI1) [(E)-4-((4-chlorobenzylidene)amino)benezenesulfonamide] and
ABEPI2 [N-tert-butyl-2-(1-tert-butyltetrazol-5-yl)sulfanylacetamide], were shown to lead to
minocycline accumulation within A. baumannii during serum growth and inhibit the efflux potential of the organism. While both compounds also inhibited the
antibiotic efflux properties of the bacterial pathogen Pseudomonas aeruginosa, they did not display significant cytotoxicity toward human cells or mammalian Ca(2+) channel inhibitory effects, suggesting that
ABEPI1 and
ABEPI2 represent promising structural scaffolds for the development of new classes of bacterial
antibiotic efflux pump inhibitors that can be used to potentiate the activities of current and future
antibiotics for the therapeutic intervention of
Gram-negative bacterial infections.