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2.A.117 The Proteobacterial Antimicrobial Compound Efflux (PACE) Family

Chlorhexidine, an antiseptic or disinfectant, is a membrane-active biocide. Hassan et al. 2013 examined the transcriptomic response of a representative nosocomial human pathogen, Acinetobacter baumannii, to chlorhexidine, to identify the primary chlorhexidine resistance elements. The most highly up-regulated genes encoded components of a major multidrug efflux system, AdeABC (TC# 2.A.6.2.40). The next most highly overexpressed gene under chlorhexidine stress was designated AceI. Orthologs of the aceI gene are conserved within the genomes of a broad range of proteobacterial species, but are also found in other bacterial phyla. Expression of aceI or its orthologs from several other γ- or β-proteobacterial species in Escherichia coli resulted in significant increases in resistance to chlorhexidine. Additionally, disruption of the aceI ortholog in Acinetobacter baylyi rendered it more susceptible to chlorhexidine. The AceI protein was localized to the membrane after overexpression in E. coli. This protein was purified, and binding assays demonstrated direct and specific interactions between AceI and chlorhexidine. Transport assays using [14C]-chlorhexidine showed that AceI mediates the energy-dependent efflux of chlorhexidine.  It was later found to  transport other drugs including benzalkonium, dequalinium, proflavine, and acriflavine. The physiological substrates are polyamines (diamines) such as cadaverine and putrescine (Hassan et al. 2019). An E15Q AceI mutant with a mutation in a conserved acidic residue, although unable to mediate chlorhexidine resistance and transport, was still able to bind chlorhexidine. AceI forms a dimeric exporter under the control of AceR (Liu et al. 2018). These data are consistent with AceI being an active chlorhexidine efflux protein and the founding member of a family of bacterial polyamine and drug efflux transporters, structurally similar to the DMT superfamily (2.A.7).

The generalized transport reaction catalyzed by AceI is:

Chlorhexidine (in)  →  chlorhexidine (out)

References associated with 2.A.117 family:

Bolla, J.R., A.C. Howes, F. Fiorentino, and C.V. Robinson. (2020). Assembly and regulation of the chlorhexidine-specific efflux pump AceI. Proc. Natl. Acad. Sci. USA 117: 17011-17018. 32636271
Hassan, K.A., L.D. Elbourne, L. Li, H.K. Gamage, Q. Liu, S.M. Jackson, D. Sharples, A.B. Kolstø, P.J. Henderson, and I.T. Paulsen. (2015). An ace up their sleeve: a transcriptomic approach exposes the AceI efflux protein of Acinetobacter baumannii and reveals the drug efflux potential hidden in many microbial pathogens. Front Microbiol 6: 333. 25954261
Hassan, K.A., Q. Liu, L.D.H. Elbourne, I. Ahmad, D. Sharples, V. Naidu, C.L. Chan, L. Li, S.P.D. Harborne, A. Pokhrel, V.L.G. Postis, A. Goldman, P.J.F. Henderson, and I.T. Paulsen. (2018). Pacing across the membrane: the novel PACE family of efflux pumps is widespread in Gram-negative pathogens. Res. Microbiol. [Epub: Ahead of Print] 29409983
Hassan, K.A., Q. Liu, P.J. Henderson, and I.T. Paulsen. (2015). Homologs of the Acinetobacter baumannii AceI transporter represent a new family of bacterial multidrug efflux systems. mBio 6:. 25670776
Hassan, K.A., S.M. Jackson, A. Penesyan, S.G. Patching, S.G. Tetu, B.A. Eijkelkamp, M.H. Brown, P.J. Henderson, and I.T. Paulsen. (2013). Transcriptomic and biochemical analyses identify a family of chlorhexidine efflux proteins. Proc. Natl. Acad. Sci. USA 110: 20254-20259. 24277845
Hassan, K.A., V. Naidu, J.R. Edgerton, K.A. Mettrick, Q. Liu, L. Fahmy, L. Li, S.M. Jackson, I. Ahmad, D. Sharples, P.J.F. Henderson, and I.T. Paulsen. (2019). Short-chain diamines are the physiological substrates of PACE family efflux pumps. Proc. Natl. Acad. Sci. USA 116: 18015-18020. 31416917
Liu, Q., K.A. Hassan, H.E. Ashwood, H.K.A.H. Gamage, L. Li, B.C. Mabbutt, and I.T. Paulsen. (2018). Regulation of the aceI multidrug efflux pump gene in Acinetobacter baumannii. J Antimicrob Chemother 73: 1492-1500. 29481596