The Influence of Blue Light and the BlsA Photoreceptor on the Oxidative Stress Resistance Mechanisms of Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a catalase-positive Gram-negative bacterial pathogen that causes severe infections among compromised patients. Among its noteworthy regulatory mechanisms, this microorganism regulates its lifestyle through the blue light using flavin (BLUF) protein BlsA. This protein regulates a diverse set of cellular processes that include, but are not limited to, motility, biofilm formation, phenylacetic acid metabolism, iron uptake, and catalase activity. We set out to determine how A. baumannii regulates catalase activity and other related oxidative stress phenotypes in response to light. Notably, because A. baumannii ATCC 17978 encodes four catalase homologs – which we refer to as KatA, KatE, KatE2, and KatG – we also aimed to show which of these enzymes exhibit light- and BlsA-dependent activity. Our work not only provides insight into the general function of all four catalase homologs and the impact of light on these functions, but also directly identifies KatE as a BlsA-regulated enzyme. We further demonstrate that the regulation of KatE by BlsA is dependent on a lysine residue that we previously demonstrated to be necessary for the regulation of surface motility. Furthermore, we show that BlsA’s five most-C-terminal residues – previously considered dispensable for BlsA’s overall function – are necessary for the light-independent and light-dependent regulation of catalase and superoxide dismutase activities, respectively. We hypothesize that these identified critical residues are necessary for BlsA’s interaction with protein partners including the transcriptional regulators Fur and BfmR. Together these data expand the understanding regarding how A. baumannii uses light as a signal to control oxidative stress resistance mechanisms that are critical for its pathophysiology.

Blue Light Sensing BlsA-Mediated Modulation of Meropenem Resistance and Biofilm Formation in Acinetobacter baumannii

“…Moreover, the modulation of a large set of genes (125 upregulated [>1.5-fold upregulation, purple colored] and 7 downregulated [<0.5-fold downregulation, green colored]) was monitored during light exposure (see Data Set S1 for the complete list of transcriptomes). The BlsA-dependent regulation of katE was also genetically demonstrated in a previous study, despite no direct biophysical evidence ( 31 ). Interestingly, many genes encoding outer membrane porins, such as OmpA, CarO, Omp33-36, PxpA, and AqpZ, were also induced during light conditions, indicating the light-dependent alteration of permeability and antibiotic resistance ( Fig.…”

“…1B ) and 5 previously reported BlsA-interacting proteins (AbaR, AcoN, KatE, Fur, and BfmR) as putative BlsA-interacting partners are depicted in Fig. 1B (orange-colored) ( 7 , 15 , 22 , 23 , 31 ). The STRING database contains data derived from an automated computational analysis that used the following gene prediction methods: neighborhood on chromosome, phylogenetic co-occurrence, and gene coexpression studies ( 33 ).…”

Host-Pathogen Interactions in Acinetobacter baumannii Infections: Mechanisms of Immune Evasion and Potential Therapeutic Targets

“…The increasing prevalence of MDR, extensive drug-resistant (XDR), and even pan-drug-resistant (PDR) strains of A. baumannii has raised concerns about limited treatment options and the need for novel antimicrobial strategies [44,45].…”

“…Researchers are exploring novel antimicrobial strategies to combat A. baumannii infections, especially those caused by MDR and XDR strains. One such approach involves the development of alternative antibiotics or antimicrobial agents that target different bacterial pathways, reducing the likelihood of cross-resistance [45]. Efforts are also underway to investigate combination therapies that synergistically enhance the efficacy of existing antibiotics, potentially overcoming resistance mechanisms.…”

“…A. baumannii has evolved mechanisms to evade host immune responses and establish persistent infections. By disrupting these interactions, researchers aim to enhance the host's ability to clear the infection and improve treatment outcomes [45,46].…”