Biology subjects

Vila, A. J.

Publications and source records attributed to Vila, A. J..

3 recordsLinked to original sources

bioRxiv2020

Cerebrospinal fluid (CSF) boosts metabolism and virulence expression factors in Acinetobacter baumannii

In a recent report by the Centers for Disease Control and Prevention (CDC), multidrug resistant (MDR) Acinetobacter baumannii is a pathogen described as an "urgent threat". Infection with this bacterium manifests as different diseases such as community and nosocomial pneumonia, bloodstream infections, endocarditis, urinary tract, wound infections, burn infections, skin and soft tissue infections, and meningitis. In particular, nosocomial meningitis, a common complication of neurosurgery caused by extensively-drug resistant (XDR) A. baumannii, is extremely challenging to manage. Therefore, it is necessary to identify signals, such as exposure to cerebrospinal fluid (CSF), that trigger expression of virulence factors that are associated with the successful establishment and progress of this infection. While a hypervirulent A. baumannii strain did not show changes in its transcriptome when incubated in the presence of CSF, a low-virulence isolate showed significant differences in gene expression and phenotypic traits. Exposure to 4% CSF caused increased expression of virulence factors such as fimbriae, pilins, and iron chelators, and virulence as determined in various model systems. Furthermore, although CSFs presence did not enhance bacterial growth, it was associated with an increase of expression of genes encoding transcription, translation, and the ATP synthesis machinery. Experiments to identify the active CSF component pointed to human serum albumin (HSA). ImportanceAcinetobacter baumannii, notorious for its multidrug resistant phenotype, overcomes nutrient deprived and desiccated conditions through its metabolic flexibility, pathogenic and physiological adaptability. Although this pathogen is commonly associated with respiratory infections, there have been a considerable amount of cases of A. baumannii bacterial meningitis. These infections are usually post-neurological surgery complications associated with high mortality rates ranging from 40 to 70%. This work describes interactions that may occur during A. baumannii infection of human cerebrospinal fluid (CSF). A. baumanniis displays capabilities to persist and thrive in a nutrient-limited environment, which also triggers the expression of virulence factors. This work also further explores A. baumanniis utilization of an essential component within CSF to trigger enhanced expression of genes associated with its pathoadaptibility in this environment.

microbiology↗

bioRxiv2020

Molecular Bases of the Membrane Association Mechanism Potentiating Antibiotic Resistance by New Delhi Metallo--Lactamase 1

Resistance to last-resort carbapenem antibiotics is an increasing threat to human health, as it critically limits therapeutic options. Metallo-{beta}-lactamases are the largest family of carbapenemases, enzymes that inactivate these drugs. Among MBLs, New Delhi metallo-{beta}-lactamase 1 has experienced the fastest and largest worldwide dissemination. This success has been attributed to the fact that NDM-1 is a lipidated protein anchored to the outer membrane of bacteria, while all other MBLs are soluble periplasmic enzymes. By means of a combined experimental and computational approach, we show that NDM-1 interacts with the surface of bacterial membranes in a stable, defined conformation, in which the active site is not occluded by the bilayer. Although the lipidation is required for a long-lasting interaction, the globular domain of NDM-1 is tuned to interact specifically with the outer bacterial membrane. In contrast, this affinity is not observed for VIM-2, a natively soluble MBL. Finally, we identify key residues involved in the membrane interaction of NDM-1, which constitute potential targets for developing therapeutic strategies able to combat resistance granted by this enzyme.

biochemistry↗

bioRxiv2020

The H-NS regulator plays a role in the stress induced by carbapenemase expression in Acinetobacter baumannii

Disruption of the histone-like nucleoid structuring protein (H-NS) was shown to affect the ability for Gram-negative bacteria to regulate genes associated with virulence, persistence, stress response, quorum sensing, biosynthesis pathways and cell adhesion. Here, we used the expression of metallo-{beta}-lactamases (MBLs) known to elicit envelope stress by the accumulation of toxic species in the periplasm to interrogate the role of H-NS in Acinetobacter baumannii, together with other stressors. Using a multidrug-resistant A. baumannii, we observed that H-NS plays a role in alleviating the stress triggered by MBL toxic precursors and counteract the effect of DNA-damaging agents, supporting its role in stress response. ImportanceCarbapenem-resistant A. baumannii (CRAB) is recognized as one of the most threatening gram-negative bacilli. H-NS is known to play a role in controlling the transcription of a variety of different genes, including those associated with stress response, persistence and virulence. In the present work, we uncovered a link between the role of H-NS in the A. baumannii stress response and its relationship with the envelope stress response and resistance to DNA-damaging agents. Overall, we posit a new role of H-NS, showing that H-NS serves to endure envelope stress that could also be a mechanism that alleviates the stress induced by MBL expression in A. baumannii. This could be an evolutionary advantage to further resist the action of carbapenems.

microbiology↗