Revised manuscript AAC 01388 - 10 1 Efflux - Mediated Antibiotic Resistance in Acinetobacter spp . 2 3 4

24 Among Acinetobacter spp., A. baumannii is the most frequently implicated in nosocomial 25 infections, in particular in intensive care units. It was initially thought that multidrug 26 resistance (MDR) in this species was mainly due to horizontal acquisition of resistance genes. 27 However, it has become recently obvious that increased expression of chromosomal genes for 28 efflux systems plays a major role in MDR. Among the five super families of pumps, 29 resistance-nodulation-division (RND) systems are the most prevalent in multiply resistant A. 30 baumannii. RND pumps typically exhibit a wide substrate range that can include antibiotics, 31 dyes, biocides, detergents, and antiseptics. Overexpression of AdeABC, secondary to 32 mutations in the adeRS genes encoding a two-component regulatory system, constitutes a 33 major mechanism of multi-resistance in A. baumannii. AdeIJK, intrinsic to this species, is 34 responsible for natural resistance but, since overexpression above a certain treshold is toxic 35 for the host, its contribution to acquired resistance is minimal. Recently described AdeFGH, 36 probably regulated by a LysR-type transcriptional regulator, also confers multidrug resistance 37 when overexpressed. Non-RND efflux systems, such as CraA, AmvA, AbeM, and AbeS have 38 been also characterized in A. baumannii as well as AdeXYZ and AdeDE in other 39 Acinetobacter spp. Finally, acquired narrow spectrum efflux pumps, such as the MFS TetA, 40 TetB, CmlA, FloR, and the SMR QacE in Acinetobacter spp. have been detected and mainly 41 encoded by mobile genetic elements. 42 on July 6, 2017 by gest httpaac.asm .rg/ D ow nladed fom