RND pumps across the genus Acinetobacter: AdeIJK is the universal efflux pump
Elizabeth M Darby1, Vassiliy N Bavro2, Steven Dunn1
1Institute of Microbiology and Infection, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Abstract:
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 often multidrug resistant. However, an additional 25 species within the genus have also been associated with infection. A. baumannii encodes six resistance nodulation division (RND) efflux pumps, the most clinically relevant class of efflux pumps for antibiotic export, but the distribution and types of RND efflux pumps across the genus is currently unknown. Sixty-four species making up the genus Acinetobacter 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 homologues 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 genus Acinetobacter. AdeIJK can export a broad range of antibiotics and provides crucial functions within the cell, for example lipid modulation of the cell membrane, and 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.
Insights
Acinetobacter species possess a fundamental efflux pump system, AdeIJK, essential for survival. Other resistance nodulation division (RND) pumps are linked to infection, offering targets for new treatments.
Area of Science:
- Microbiology
- Molecular Biology
- Genomics
Background:
- Acinetobacter species, including the multidrug-resistant A. baumannii, cause significant human infections.
- While A. baumannii has multiple resistance nodulation division (RND) efflux pumps, their distribution across the Acinetobacter genus is unknown.
- RND efflux pumps are crucial for antibiotic export and resistance in bacteria.
Purpose of the Study:
- To investigate the distribution and types of RND efflux pumps across the Acinetobacter genus.
- To identify conserved RND systems essential for Acinetobacter survival.
- To understand the role of specific RND pumps in Acinetobacter-associated infections.
Main Methods:
- Genomic analysis of 64 Acinetobacter species to identify RND systems.
- Development of a novel method to predict RND protein numbers using conserved residues.
- Genomic, structural, and phenotypic analyses to confirm RND system homology.
Main Results:
- The AdeIJK/AdeXYZ system is conserved across all studied Acinetobacter species, suggesting it's a fundamental RND system.
- A novel method accurately predicted RND protein numbers, revealing variations within and across species.
- Infected-associated species tend to encode more RND pumps, with systems like AdeABC and AdeFGH found in a subset.
Conclusions:
- AdeIJK is the core RND efflux system in Acinetobacter, vital for survival, homeostasis, and likely antibiotic resistance.
- Additional RND systems are associated with infection and may represent targets for therapeutic intervention.
- Understanding RND pump mechanisms can guide the development of treatments to overcome efflux-mediated resistance in Acinetobacter infections.
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