An Update on the Acinetobacter baumannii Regulatory Circuitry

Wood, Cecily R.; Mack, Lydia; Actis, Luis A.

doi:10.1016/j.tim.2018.05.005

Cited by 12 publications

(9 citation statements)

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“…The study of the factors controlling the expression of virulence factors is crucial for the development of novel antimicrobial strategies in antibiotic-resistant pathogens like A. baumannii. Multiple transcriptional regulatory systems are involved in the persistence and pathogenesis of this species (Wood et al, 2018a;De Silva and Kumar, 2019). Among these regulatory circuits, QS has emerged as an interesting target for the control of virulence factors (Zhang et al, 2017;Mayer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In Acinetobacter spp. a complex network of sensors controls the expression of virulence factors integrating intra-and extracellular signals (Harding et al, 2018;Wood et al, 2018a;De Silva and Kumar, 2019). Among these, quorum sensing (QS), a mechanism of control of gene expression dependent on bacterial cell density, seems to play a central role, constituting an interesting target for the development on antimicrobial strategies.…”

Section: Introductionmentioning

confidence: 99%

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Quorum Sensing as a Target for Controlling Surface Associated Motility and Biofilm Formation in Acinetobacter baumannii ATCC® 17978TM

et al. 2020

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The important nosocomial pathogen Acinetobacter baumannii presents a quorum sensing (QS) system (abaI/abaR) mediated by acyl-homoserine-lactones (AHLs) and several quorum quenching (QQ) enzymes. However, the roles of this complex network in the control of the expression of important virulence-related phenotypes such as surface-associated motility and biofilm formation is not clear. Therefore, the effect of the mutation of the AHL synthase AbaI, and the exogenous addition of the QQ enzyme Aii20J on surface-associated motility and biofilm formation by A. baumannii ATCC R 17978 TM was studied in detail. The effect of the enzyme on biofilm formation by several multidrug-resistant A. baumannii clinical isolates differing in their motility pattern was also tested. We provide evidence that a functional QS system is required for surface-associated motility and robust biofilm formation in A. baumannii ATCC R 17978 TM. Important differences were found with the well-studied strain A. nosocomialis M2 regarding the relevance of the QS system depending on environmental conditions The in vitro biofilm-formation capacity of A. baumannii clinical strains was highly variable and was not related to the antibiotic resistance or surface-associated motility profiles. A high variability was also found in the sensitivity of the clinical strains to the action of the QQ enzyme, revealing important differences in virulence regulation between A. baumannii isolates and confirming that studies restricted to a single strain are not representative for the development of novel antimicrobial strategies. Extracellular DNA emerges as a key component of the extracellular matrix in A. baumannii biofilms since the combined action of the QQ enzyme Aii20J and DNase reduced biofilm formation in all tested strains. Results demonstrate that QQ strategies in combination with other enzymatic treatments such as DNase could represent an alternative approach for the prevention of A. baumannii colonization and survival on surfaces and the prevention and treatment of infections caused by this pathogen.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quorum Sensing as a Target for Controlling Surface Associated Motility and Biofilm Formation in Acinetobacter baumannii ATCC® 17978TM

et al. 2020

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“…Regrowth at the highest concentration and its loss after as little as two passages without FDC confirm the adaptability of this species to the surrounding environment, responding to a myriad of intra- and extra-cellular signals [25]. All these regulatory circuitries, widely represented in the genome of this microorganism, were evoked to explain the emergence of resistant cells expressing distinct and critical phenotypes - for example, becoming resistant - in order to survive and adapt to hostile situations.…”

Section: Discussionmentioning

confidence: 78%

Acinetobacter baumannii and cefiderocol between cidality and adaptability

Stracquadanio

Bonomo

Marino

et al. 2022

Preprint

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Among the bacterial species included in the ESKAPE group, Acinetobacter baumannii is of great interest due to its intrinsic and acquired resistance to many antibiotic classes and its ability to infect different body districts. Cefiderocol is a novel cephalosporin active against Gram-negative bacteria with promising efficacy on A. baumannii infections, but some studies have reported therapeutic failures even in the presence of susceptible A. baumannii strains. This study aims to investigate the interactions between cefiderocol and ten A. baumannii strains with different susceptibility profiles to this drug. We confirmed diverse susceptibility profiles in the strains, with resistance values close to the EUCAST-proposed breakpoints. MBC/MIC (minimal bactericidal concentration/minimal inhibitory concentration) ratios, demonstrated bactericidal activity of the drug; on the other hand, bacterial regrowth was evident after exposition to cefiderocol, as were changes in the shape of colonies and bacterial cells. A switch to a non-susceptible phenotype in the presence of high cefiderocol concentrations was found as adaptation mechanisms implemented by these A. baumannii strains to overcome the cidal activity of this antibiotic, also confirmed by the presence of heteroresistant, unstable subpopulations. As our isolates harbored numerous β-lactamase genes, β-lactamase inhibitors showed the ability to restore the antimicrobial activity of cefiderocol regardless of the different non-susceptibility levels of the tested strains. These in vitro results, can sustain the concept of using combination therapy to eliminate drug-adapted subpopulations and regain full cefiderocol activity in this difficult-to-treat species.

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“…Signal transduction mechanisms in bacteria play a crucial role in adapting to environmental changes. TCSs are one of the most ubiquitous signal transduction systems present in bacteria that help them sense and adapt to the environmental conditions (Alm et al, 2006; Wood et al, 2018). TCSs therefore play a role in bacterial adaptive responses which can lead to the modulation of their antibiotic susceptibility and virulence.…”

Section: Introductionmentioning

confidence: 99%

Signal Transduction Proteins in Acinetobacter baumannii: Role in Antibiotic Resistance, Virulence, and Potential as Drug Targets

Silva

Kumar

2019

Front. Microbiol.

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Acinetobacter baumannii is a notorious pathogen in health care settings around the world, primarily due to high resistance to antibiotics. A. baumannii also shows an impressive capability to adapt to harsh conditions in clinical settings, which contributes to its persistence in such conditions. Following their traditional role, the Two Component Systems (TCSs) present in A. baumannii play a crucial role in sensing and adapting to the changing environmental conditions. This provides A. baumannii with a greater chance of survival even in unfavorable conditions. Since all the TCSs characterized to date in A. baumannii play a role in its antibiotic resistance and virulence, understanding the underlying molecular mechanisms behind TCSs can help with a better understanding of the pathways that regulate these phenotypes. This can also guide efforts to target TCSs as novel drug targets. In this review, we discuss the roles of TCSs in A. baumannii, their molecular mechanisms, and most importantly, the potential of using small molecule inhibitors of TCSs as potential novel drug targets.

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An Update on the Acinetobacter baumannii Regulatory Circuitry

Cited by 12 publications

References 10 publications

Quorum Sensing as a Target for Controlling Surface Associated Motility and Biofilm Formation in Acinetobacter baumannii ATCC® 17978TM

Quorum Sensing as a Target for Controlling Surface Associated Motility and Biofilm Formation in Acinetobacter baumannii ATCC® 17978TM

Acinetobacter baumannii and cefiderocol between cidality and adaptability

Signal Transduction Proteins in Acinetobacter baumannii: Role in Antibiotic Resistance, Virulence, and Potential as Drug Targets

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