AbOmpA in Acinetobacter baumannii: exploring virulence mechanisms of outer membrane-integrated and outer membrane vesicle-associated AbOmpA and developing anti-infective agents targeting AbOmpA

Abstract

Acinetobacter baumannii is notorious for its antimicrobial resistance and its potential to cause epidemics in hospital settings, which pose a global health threat. Although this microorganism is traditionally considered a low-virulence pathogen, extensive research has been conducted on its virulence and pathogenesis in recent years. Advances in understanding the virulence mechanisms of A. baumannii have prompted a shift in the development of anti-infective agents. The outer membrane protein A (AbOmpA) of A. baumannii is a key virulence factor both in vitro and in vivo. AbOmpA exists in three forms: outer membrane-integrated AbOmpA, outer membrane vesicle (OMV)-associated AbOmpA, and free proteins. Given that outer membrane-integrated AbOmpA has been implicated in the virulence and antimicrobial resistance of A. baumannii, many studies have focused on outer membrane-integrated AbOmpA as a therapeutic target for combating drug-resistant A. baumannii, and have led to the discovery of small molecules, polypeptides, and antimicrobial peptides targeting AbOmpA. However, the pathophysiological role of OMV-associated AbOmpA and its impact on AbOmpA-targeting agents remain unclear. This review summarizes the current knowledge of AbOmpA and critically discusses OMV-associated AbOmpA in relation to virulence and its potential impact on AbOmpA-targeted therapies to provide a better understanding of AbOmpA for the development of novel therapeutics against A. baumannii.

Keywords: Acinetobacter baumannii; Anti-infective agent; Outer membrane protein A; Outer membrane vesicle; Virulence factor.

Fig. 1

Three-dimensional structural representation of AbOmpA provides a comprehensive overview of its structural organization. a Ribbon diagram of the full-length homology model of AbOmpA. The N-terminal β-barrel domain (top) is embedded in the outer membrane, while the C-terminal periplasmic domain (bottom) extends into the periplasmic space. b Electrostatic surface potential of the modeled AbOmpA structure, showing the distribution of surface charges across both domains. Red and blue indicate negatively and positively charged regions, respectively. c Close-up view of the β-barrel domain, highlighting key extracellular loops labeled (Loop 1–Loop 4). Two views are shown, rotated by 90° to reveal structural details. d Side and top views of the periplasmic domain, emphasizing key residues Arg286 and Asp271, which are involved in intramolecular interactions and may play roles in periplasmic signaling. The α-helices are shown in red, β-strands in cyan, and loop regions in white. The structural model was generated using the Schrödinger 2024–3 suite via homology modeling, with E. coli OmpA (PDB ID: 1QJP) as the template. Sequence alignment revealed approximately 36.4% identity and 52% similarity between the target and template sequences. The reliability of the predicted structure was further validated by a 100-ns molecular dynamics simulation in explicit solvent, confirming conformational stability with a consistent backbone RMSD (1.5 ~ 2.0 Å) and stable radius of gyration

Fig. 2

Schematic representation of host cell death induced by OMV-associated AbOmpA. AbOmpA binds to the VDAC on the mitochondrial outer membrane. This leads to an increased mitochondrial transmembrane potential (ΔΨ), ROS production, and inner membrane hyperpolarization. These events trigger the opening of the mitochondrial permeability transition pore (MPTP), resulting in mitochondrial swelling, loss of membrane integrity, and cytochrome C release, which initiates apoptotic cascade. In parallel, AbOmpA activates DRP1, promoting its accumulation on mitochondria, further enhancing ROS production and mitochondrial fragmentation. Released cytochrome C activates apoptotic protease activating factor 1 (Apaf1), forming the apoptosome complex and subsequently activating caspase-3 and -7 to execute apoptosis. Upon mitochondrial outer membrane rupture, apoptosis inducing factor (AIF) is translocated to the nucleus, contributing to apoptosis. Additionally, AbOmpA can enter the nucleus via its nuclear localization signal (NLS), where it degrades DNA through its DNase I activity. Biorender software (Biorender.com) was used to create figure

Fig. 3

Innate immune response induced by A. baumannii OMVs and OMV-associated AbOmpA. A. baumannii OMVs elicit a pro-inflammatory response, primarily mediated by AbOmpA. AbOmpA interacts with the cell surface receptor TLR2, leading to recruitment of the adaptor protein MyD88 and activation of the NF-κB and MAPK signaling pathways, including ERKs, JNKs, and p38. This signaling cascade promotes the transcription of genes encoding pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-8, MCP-1, TNF-α, and MIP-1α. Additionally, activation of the NLRP3 inflammasome leads to the cleavage of procaspase-1 into active caspase-1, which subsequently processes pro-IL-1β into its active form, amplifying the inflammatory response. Biorender software (Biorender.com) was used to create figure

Fig. 4

Immune modulation by A. baumannii OMVs and OMV-associated AbOmpA. A. baumannii OMVs, and particularly OMV-associated AbOmpA, modulate the adaptive immune response by interacting with antigen-presenting cells, such as DCs. AbOmpA binds to pattern recognition receptors (PRRs) on antigen-presenting cells (APCs), triggering signaling pathways that upregulate antigen-presenting molecules, including MHC class II, as well as co-stimulatory molecules such as CD40, CD54, and B7. These activated APCs present OMV-derived antigens to CD4⁺ T cells, promoting TH1 cell activation and proliferation. In turn, activated TH cells stimulate B cells, driving their differentiation into plasma cells that secrete OMV-specific antibodies. During this process, APCs also release pro-inflammatory cytokines, including IL-12 and IFN-γ, further enhancing the immune response. Biorender software (Biorender.com) was used to create figure