TY - UNPB
T1 - RND pumps across the Acinetobacter genus; AdeIJK is the ancestral efflux system
AU - Darby, Elizabeth M.
AU - Bavro, Vassiliy N.
AU - Dunn, Steven
AU - McNally, Alan
AU - Blair, Jessica M. A.
PY - 2022/10/19
Y1 - 2022/10/19
N2 - Acinetobacter are generally soil-dwelling organisms that can also cause serious human infections. A. baumannii is one of the most common causative agents of Acinetobacter infections and is extensively drug resistant. However, an additional 25 species within the genus have also been associated with infection. A. baumannii encodes 6 RND efflux pumps, the most clinically relevant class of efflux pumps for antibiotic export, however the distribution and types of RND efflux pumps across the genus is currently unknown. Sixty-three species making up the Acinetobacter genus were searched for RND systems within their genomes. We also developed a novel method using conserved RND residues to predict the total number of RND proteins including currently undescribed RND pump proteins. The total number of RND proteins differed both within a species and across the genus. Species associated with infection tended to encode more pumps. AdeIJK/AdeXYZ was found in all searched species of Acinetobacter, and through genomic, structural and phenotypic work we show that these genes are actually orthologues of the same system. This interpretation is further supported by structural analysis of the potential drug-binding determinants of the associated RND-transporters, which reveal their close similarity to each other, and distinctiveness from other RND-pumps in Acinetobacter, such as AdeB. Therefore, we conclude that AdeIJK is the fundamental RND system for species in the Acinetobacter genus. AdeIJK can export a broad range of antibiotics and provides crucial functions within the cell, for example lipid modulation of the cell membrane, therefore it is likely that all Acinetobacter require AdeIJK for survival and homeostasis. In contrast, additional RND systems, such as AdeABC and AdeFGH were only found in a subset of Acinetobacter, that are associated with infection. By understanding the roles and mechanisms of RND efflux systems in Acinetobacter, treatments for infections can avoid efflux-mediated resistance and improve patient outcomes.
AB - Acinetobacter are generally soil-dwelling organisms that can also cause serious human infections. A. baumannii is one of the most common causative agents of Acinetobacter infections and is extensively drug resistant. However, an additional 25 species within the genus have also been associated with infection. A. baumannii encodes 6 RND efflux pumps, the most clinically relevant class of efflux pumps for antibiotic export, however the distribution and types of RND efflux pumps across the genus is currently unknown. Sixty-three species making up the Acinetobacter genus were searched for RND systems within their genomes. We also developed a novel method using conserved RND residues to predict the total number of RND proteins including currently undescribed RND pump proteins. The total number of RND proteins differed both within a species and across the genus. Species associated with infection tended to encode more pumps. AdeIJK/AdeXYZ was found in all searched species of Acinetobacter, and through genomic, structural and phenotypic work we show that these genes are actually orthologues of the same system. This interpretation is further supported by structural analysis of the potential drug-binding determinants of the associated RND-transporters, which reveal their close similarity to each other, and distinctiveness from other RND-pumps in Acinetobacter, such as AdeB. Therefore, we conclude that AdeIJK is the fundamental RND system for species in the Acinetobacter genus. AdeIJK can export a broad range of antibiotics and provides crucial functions within the cell, for example lipid modulation of the cell membrane, therefore it is likely that all Acinetobacter require AdeIJK for survival and homeostasis. In contrast, additional RND systems, such as AdeABC and AdeFGH were only found in a subset of Acinetobacter, that are associated with infection. By understanding the roles and mechanisms of RND efflux systems in Acinetobacter, treatments for infections can avoid efflux-mediated resistance and improve patient outcomes.
U2 - 10.1101/2022.10.19.512856
DO - 10.1101/2022.10.19.512856
M3 - Preprint
BT - RND pumps across the Acinetobacter genus; AdeIJK is the ancestral efflux system
PB - bioRxiv
ER -