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. 2026 Sep 29;208(10):e00360-26. doi: 10.1128/jb.00360-26

A minimalist opportunist: the emergence of Acinetobacter baumannii

Manon Janet-Maitre 1,✉,3, Mario F Feldman 1,✉
Editor: George O'Toole2
PMCID: PMC13689556  PMID: 42809376

ABSTRACT

Acinetobacter baumannii has evolved from a relatively overlooked nosocomial pathogen into one of the most concerning multidrug-resistant threats worldwide. Its global dissemination, accelerated by healthcare-associated transmission and the emergence of carbapenem-resistant strains, has established A. baumannii as a critical priority pathogen. While initially studied primarily through the lens of antimicrobial resistance, growing evidence indicates that the remarkable success of A. baumannii cannot be attributed to resistance alone. Unlike many classical bacterial pathogens, A. baumannii lacks an extensive arsenal of virulence factors and major secretion systems. Instead, its success relies on a highly effective “persist and resist” strategy, combining intrinsic tolerance, extensive genomic plasticity, metabolic adaptability, and multilayered regulatory networks that enable survival under severe environmental and host-imposed stresses. This apparent simplicity, coupled with exceptional resilience, makes A. baumannii a particularly informative system for understanding how limited pathogenic determinants can generate profound clinical success. In this review, we highlight the key biological features that have established A. baumannii as a model system. We discuss milestone discoveries that have reshaped our understanding of its pathogenesis, emphasizing how this pathogen leverages adaptability rather than an extensive virulence arsenal to succeed as an opportunistic pathogen, expanding the field beyond antibiotic resistance toward broader questions of host-pathogen interaction and environmental adaptation. Finally, we outline major open questions in the field, including the contribution of intracellular reservoirs to chronic infection and treatment failure. Together, these perspectives position A. baumannii as a unique system for investigating how a seemingly minimalist pathogen achieves extraordinary adaptability and clinical success.

KEYWORDS: opportunistic pathogen, antibiotic resistance, Acinetobacter baumannii, stress response

INTRODUCTION

In the early 20th century, Martinus Beijerinck first described members of the Acinetobacter genus, which he named Micrococcus calcoaceticus. The name Acinetobacter (from the Greek akinetos, meaning “non-motile”) was proposed by Brisou and Prévot in 1954 and was later formally recognized by the Subcommittee on the Taxonomy of Moraxella and Allied Bacteria in 1971 (1). Although Acinetobacter spp. lack flagella and were initially classified as non-motile, it is now well established that they can exhibit forms of surface-associated motility (2). Acinetobacter species are ubiquitous in the environment; however, the opportunistic pathogen A. baumannii is predominantly associated with hospital settings.

As early as the 1970s, A. baumannii was recognized as a nosocomial pathogen due to its ability to adhere to plastic medical devices such as catheters and endotracheal tubes, as well as its capacity to withstand desiccation and persist on hospital surfaces (3). A. baumannii causes a wide range of infections in critically ill patients, including respiratory tract infections, particularly ventilator-associated pneumonia, as well as bloodstream, wound, and urinary tract infections (UTIs), often associated with catheter use (4, 5). These infections are especially prevalent in intensive care units (ICUs). Its rapid acquisition of resistance to multiple classes of antibiotics, including last-line carbapenems, has been documented since the 1980s, leading to the emergence of carbapenem-resistant A. baumannii (CRAB) (6, 7).

A. baumannii gained global attention during the Iraq War with the United States (from 2003 onward), where it earned the nickname “Iraqibacter”. Combat-related wounds and burns, combined with strained healthcare conditions, facilitated intra-hospital transmission and the spread of multidrug-resistant (MDR) strains (8–10). The repatriation of military and civilian casualties to the United Kingdom and the United States contributed to the global dissemination of these resistant strains, leading to outbreaks in hospitals worldwide (11–13).

Since the 2000s, A. baumannii has been recognized as one of the ESKAPEE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp.), a group of bacterial pathogens known for their ability to evade antimicrobial treatments. It is also classified as a “critical priority” pathogen by the World Health Organization due to the alarming rise in multidrug-resistant (MDR), extensively drug-resistant (XDR), and even pan-drug-resistant strains. In some countries, more than 80% of A. baumannii isolates exhibit resistance to commonly used antibiotics (14, 15).

More recently, the COVID-19 pandemic, caused by SARS-CoV-2, has further exacerbated the burden of A. baumannii infections. Severe COVID-19 cases often require intensive care, increasing the risk of secondary infections, particularly respiratory, bloodstream, and urinary tract infections (16, 17). Invasive mechanical ventilation significantly elevates the risk of ventilator-associated pneumonia, frequently due to secondary bacterial infections, with A. baumannii being among the most prevalent pathogens (17). Increased ICU occupancy, overwhelmed healthcare systems, and widespread antibiotic use during the pandemic contributed to outbreaks of MDR and CRAB strains (18, 19).

As a result, what was once considered an opportunistic hospital pathogen has evolved into a globally disseminated and highly resilient threat. With over 300,000 deaths attributable to A. baumannii in 2019, prolonged hospital stays averaging around 30 days (20, 21), high mortality rates, and limited therapeutic options, this pathogen represents a major burden on modern healthcare systems. There is an urgent need to better understand its biology and pathogenicity in order to develop effective alternative treatments.

FEATURES THAT MAKE A. BAUMANNII A GREAT MODEL SYSTEM

The establishment of A. baumannii as a model system occurred alongside its rapid global spread, raising growing concern about antimicrobial resistance. This prompts a key question: why has A. baumannii developed multidrug resistance at such an exceptional pace?

Part of the answer lies in its intrinsic resistance. A. baumannii exhibits low outer membrane permeability, driven in part by the restrictive nature of outer membrane proteins such as OmpA (22–25), and expresses multiple efflux systems, some of which are constitutively active, that can actively expel a wide range of antibiotics (26–28).

Beyond these baseline defenses, its remarkable evolutionary success is driven by the combination of natural competence and high genomic plasticity (29). Mobile genetic elements (MGEs), including transposons and insertion sequences (ISs), play a central role in this process. While many A. baumannii isolates are not naturally competent, strains capable of natural transformation can acquire large fragments of exogenous DNA, potentially carrying multidrug-resistance determinants (30). These are then efficiently integrated, rearranged, and expressed within a highly recombinogenic genome, supported by mobile elements (29). Insertion sequences (ISs), a class of dynamic MGEs, play an important role in A. baumannii antibiotic resistance. For example, the insertion sequence ISAba1 has been shown to modulate A. baumannii antibiotic resistance in different ways, including its frequent insertion upstream of the chromosomal β-lactamase genes blaOXA-51, blaOXA-23, blaADC, and ampC leading to their upregulation and subsequent increased resistance to carbapenems and cephalosporins (29, 31–34). Additionally, insertion of ISAba1 into the adeS gene, upstream of the adeABC operon, can lead to constitutive overexpression of the AdeABC efflux pump, thereby enhancing antibiotic resistance (Fig. 1) (35). Other genomic islands, including AbaR, can also modulate competence by inserting into comM, a critical gene in A. baumannii competence, further illustrating the complexity of these genomic interactions (36). Under antibiotic pressure, this combination of natural transformation and high genetic plasticity enables the rapid evolution of extensive, and sometimes unprecedented, resistance profiles. Additionally, the acquisition of plasmids harboring antibiotic resistance cassettes further drives A. baumannii genomic plasticity (37, 38).

Fig 1.

Diagram of A. baumannii showing the key mechanisms of antibiotic resistance, stress responses driving persistence in hopital settings (including dessication and oxidative stress tolerance), genomic plasticity, and virulence.

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The toolkit of a successful opportunistic pathogen. A. baumannii relies on a limited yet highly integrated set of traits that collectively enable persistence in clinical environments and opportunistic infection. These include antibiotic resistance (A), stress responses involved in the success of A. baumannii in hospital settings (B), genomic plasticity (C), and host interaction and virulence strategies (D). aa, amino acids; ATB, antibiotics; IS, insertion sequences; LOS, lipooligosaccharide; PAA, phenylacetic acid; T1SS, type 1 secretion system; T2SS, type 2 secretion system; TCS, two-component systems; Tn, transposons.

In Gram-negative bacteria, resistance to colistin is commonly mediated by modifications of the lipid A component of lipopolysaccharide (LPS) (39). In A. baumannii, this typically involves the addition of a phosphoethanolamine (pEtN) moiety to the LPS by the phosphoethanolamine transferase EptA (PmrC), which reduces the negative charge of the bacterial outer membrane and decreases colistin binding (40). This modification is regulated by the two-component regulatory system (TCS) PmrAB, and clinical resistance to colistin is most commonly associated with mutations in pmrAB that result in constitutive activation of the system (41). A. baumannii can also employ similar LPS-modifying mechanisms. However, it additionally possesses a distinct strategy: it can completely lose its lipooligosaccharide (LOS), an LPS devoid of O-antigen, thereby effectively eliminating the target of colistin altogether (42, 43).

Understanding how these diverse mechanisms interact has been greatly facilitated by technological advances. In particular, next-generation sequencing has transformed A. baumannii research by enabling high-resolution phylogenetic analyses, tracking the spread of resistant lineages, and supporting the development of molecular tools. As a genetically tractable organism, it has become increasingly accessible for experimental studies.

These advances have, in turn, shifted the focus from resistance alone to a broader understanding of pathogenesis. Although individual virulence factors were described earlier, more systematic investigations into A. baumannii pathogenicity have only gained momentum in recent years. In parallel, the development of improved animal models has provided deeper insight into host-pathogen interactions and disease mechanisms.

Overall, although A. baumannii may not be a traditional model for understanding conserved processes and virulence strategies, its unique lifestyle and minimalist approach to pathogenesis, largely centered on its ability to withstand and adapt to diverse stresses, provide valuable insights into a distinct class of opportunistic pathogens. As a model system, studying A. baumannii pathogenesis challenges traditional concepts of virulence and may help broaden our understanding of opportunistic pathogens that rely on a limited repertoire of classical virulence factors yet remain highly successful pathogens.

UNIQUE FEATURES AND MILESTONE DISCOVERIES

Persistence in clinical settings

Since its emergence in clinical environments, A. baumannii has proven to be exceptionally well adapted to withstand and persist under hospital conditions. A defining feature of this pathogen is its ability to maintain viability under nutrient-deprived and desiccating conditions. While all strains exhibit substantial tolerance to desiccation, certain isolates can survive for several months in dry environments (44–46).

This phenotype is governed by a complex regulatory network, prominently involving the TCS BfmRS (47). Among its downstream effectors are the hydrophilins DtpA and DtpB, which play key roles in desiccation tolerance (46). Notably, recombinant DtpA has been shown to enhance desiccation resistance and protect enzymatic activity from inactivation. Additional factors contributing to this process include acylation of lipid A within LOS, which may increase membrane fluidity, as well as the presence of the capsular polysaccharide (48, 49).

Beyond environmental persistence, A. baumannii is a major contributor to medical device-associated infections, largely due to its ability to form robust biofilms on abiotic surfaces such as endotracheal tubes and stainless steel (50). These biofilms confer increased tolerance to environmental stresses (50, 51). Biofilm formation is driven primarily by the production of the extracellular matrix polymer poly-β-1,6-N-acetylglucosamine (PNAG) (52), in combination with surface-associated structures. Among these, Csu, a chaperone-usher pili (CUP), is critical for initial attachment and biofilm formation on abiotic surfaces (53–55). Additional CUP pili have been identified in many strains. These include Abp1 (or CUP1) and Abp2 (or CUP2) (56). Other surface appendages, including Acinetobacter trimeric autotransporter adhesin (Ata), have also been implicated in biofilm formation. Although their precise roles remain less clearly defined (Fig. 1) (57).

Importantly, most studies on biofilm formation have been conducted in vitro. However, in vivo models provide additional insight: insertion of medical tubing into the urinary and respiratory tracts leads to rapid coating with host proteins such as fibrin and fibrinogen (58–60). In this context, A. baumannii relies on specialized surface structures to colonize the device, including the invasin InvL, Ata, and the CUP pili Abp1 and Abp2, which mediate binding to fibrinogen-coated catheters and are essential for colonization during catheter-associated urinary tract infections (CAUTIs) (56, 61). Remarkably, the structural tip adhesin of the Abp1 pilus functions as a lectin, binding directly to the complex N-linked sugar moieties present on the fibrinogen molecule (56).

A. baumannii: a paradigm of stress-adapted persistence

Rather than relying on a single dominant virulence determinant, this pathogen combines intrinsic tolerance with highly coordinated regulatory responses, enabling persistence across fluctuating and often hostile conditions. This versatility underpins its ability to thrive in both clinical and environmental reservoirs.

Oxidative and iron-limiting stress resilience

A. baumannii frequently encounters high levels of reactive oxygen species (ROS), arising from disinfectants such as hydrogen peroxide, desiccation, and host immune defenses during infection. Its notable tolerance to ROS relies on a robust arsenal of detoxifying enzymes, including catalases (KatG and KatE; Fig. 1) and superoxide dismutases, largely controlled by the global regulator OxyR (62, 63). More recently, the heat shock protein HslJ was shown to contribute to H2O2 tolerance in an OxyR-dependent manner (64). In addition, insertion of ISAba1 upstream of katG can drive ~20-fold overexpression, further enhancing hydrogen peroxide tolerance (65). Together, these mechanisms illustrate both regulatory and genetic routes to oxidative stress resilience.

Iron limitation represents another major challenge during infection. As transition metals such as iron are essential for virtually all forms of life, hosts restrict their availability through a process termed nutritional immunity to limit pathogen growth (66). A. baumannii, however, has evolved multiple strategies to overcome this constraint. Notably, it can produce up to ten distinct siderophores, specialized iron-chelating molecules (67). The best-characterized siderophore is the catechol-hydroxamate acinetobactin, which exists in two forms depending on environmental pH (68, 69) and is required for full virulence (70). The acinetobactin biosynthetic genes are highly conserved across A. baumannii strains. In addition, the bacterium produces other siderophores, including the conserved baumannoferrin and the rarer fimsbactins, although their precise roles in physiology and virulence remain less well defined (67, 71, 72). The importance of siderophore-mediated iron uptake has recently been exploited therapeutically, with the development of siderophore-antibiotic conjugates that hijack these uptake systems to restore antibacterial activity. A prominent example is cefiderocol, a siderophore cephalosporin novel antibiotic (73).

Capsule and phenotypic diversity

The capsule is a central virulence determinant in A. baumannii, conferring protection against desiccation, disinfectants, antibiotics, and host innate immunity, including resistance to serum complement (69, 74–77). Capsule biosynthesis is encoded by the highly variable K locus, with more than 200 identified types, underscoring extensive capsular diversity (78). Notably, the capsule also serves as a primary receptor for bacteriophages, contributing to restricted phage host range (79).

At the population level, A. baumannii exploits phase variation to generate phenotypic heterogeneity within isogenic populations. This bet-hedging strategy enables isogenic populations to diversify into subpopulations with distinct traits (80). In strain AB5075, two colony morphotypes, opaque and translucent, were described (48). These variants, which have also been observed in numerous other A. baumannii strains and clinical isolates but not in the domesticated strain ATCC 17978 (48, 81), differ markedly in capsule thickness, virulence, motility, biofilm formation, and antibiotic resistance. Opaque variants are hypervirulent, exhibiting increased capsule production and competitive fitness in vivo (81, 82). Switching frequency is influenced by cell density and regulated by the TetR-type regulator ABUW_1645 (82). This phenotype was also observed in other strains of A. baumannii. However, the molecular mechanisms and environmental triggers governing this switch remain incompletely understood.

Importantly, phase variation has practical implications for experimental design. Detection requires plating >200 CFU on low-agar media and visualization under specific lighting conditions (48). Given this inherent heterogeneity, experimental workflows should account for population diversity, either by quantifying switching frequencies or by inoculating cultures from multiple colonies to avoid biased phenotypic selection.

PAA: metabolism meets signaling

Beyond structural and phenotypic adaptations, A. baumannii integrates stress responses with metabolism and signaling networks. Canonical secondary messengers, including cAMP, c-di-GMP, and (p)ppGpp, contribute to global regulatory control (83–85). In parallel, the phenylacetic acid (PAA) degradation pathway has emerged as a key link between metabolism and stress adaptation. The paa operon is consistently identified as highly regulated across diverse conditions, including biofilm growth and environmental stress (86, 87), suggesting a central physiological role. Increasing evidence indicates that PAA functions beyond metabolism as a signaling molecule influencing biofilm formation, pili expression, antibiotic tolerance, and oxidative stress resistance, with measurable contributions to virulence (88). Functional studies further support this role, as disruption of paa genes impairs intracellular survival and desiccation tolerance by promoting entry into a viable but non-culturable (VBNC) state (89, 90). Despite these advances, the integration of PAA signaling within broader regulatory networks remains to be clarified.

Regulatory hubs

The versatility of A. baumannii ultimately relies on integrated regulatory systems that fine-tune stress responses. Among these, the TCSs BfmRS and GacSA act as central hubs. BfmRS controls a large regulon (>300 genes) and governs key traits including oxidative, osmotic, and heat stress responses, as well as capsule production, Csu pili assembly, and siderophore synthesis (91–94). These functions directly contribute to serum resistance and antibiotic tolerance. GacSA similarly regulates virulence-associated phenotypes such as biofilm formation and motility, and notably modulates expression of the paa operon (91, 95). In parallel, N-acyl homoserine lactone (AHL)-based quorum sensing further shapes virulence and community behaviors, although this system has been extensively reviewed elsewhere (96–98).

Collectively, A. baumannii persistence emerges from the interplay between intrinsic tolerance mechanisms, phenotypic diversification, metabolic flexibility, and multilayered regulatory control. These systems do not act in isolation but form an interconnected network that allows rapid adaptation to stress. Elucidating how these pathways are integrated and identifying points of vulnerability within this network remain a key challenges for understanding and ultimately controlling this highly resilient pathogen.

Pathogenesis strategies of A. baumannii

In recent years, focus has shifted to the study of the pathogenicity and virulence of A. baumannii. This organism can be considered a “minimalist” pathogen: rather than relying on a large arsenal of canonical virulence factors, it leverages a limited set of determinants combined with versatility and highly efficient stress response mechanisms to survive and proliferate in host environments. Here, we do not aim to comprehensively review all described virulence factors, which have been extensively covered elsewhere (69, 91). Instead, we highlight key features that underpin the success of A. baumannii as a pathogen.

Adhesion to biotic surfaces

Adhesion to host cells represents a critical early step in A. baumannii pathogenesis. Individual strains express distinct repertoires of surface adhesins, enabling fine-tuned interactions with specific host tissues. Well-characterized factors involved in adhesion include the biofilm-associated protein Bap, the autotransporter Ata, and the outer membrane protein OmpA (99–101). More recently, the twin-arginine translocation (Tat) system has also been implicated in adhesion to both epithelial (A549) and endothelial (EA.hy926) cells (102). Additionally, InvL has been shown to mediate adhesion to kidney (MDCK) and bladder (5637/HTB-9) epithelial cells (Fig. 1) (61).

Other factors remain more controversial. Early studies suggested that the Csu CUP pili were required for attachment to abiotic surfaces but not to biotic ones (103). However, more recent work indicates a role for Csu pili in adhesion to epithelial cells and in lung colonization in vivo (104, 105). These discrepancies likely reflect strain-dependent differences and variable expression across conditions, highlighting the need for further investigation to clarify the role of Csu in host cell adhesion.

A facultative intracellular lifestyle

Increasing evidence now supports the view of A. baumannii as a facultative intracellular pathogen. Across multiple models, some strains and clinical isolates of A. baumannii have been shown to invade and replicate within diverse eukaryotic cells, including epithelial cells, endothelial cells, and macrophages (100, 106, 107) reviewed in reference 108. In vivo, Acinetobacter-containing vacuoles (ACVs) have been observed in infected mouse lungs. In macrophages, early resistance to acidic pH is critical for ACV establishment. Certain strains, such as Ab398, subsequently neutralize vacuolar acidification through the production of ammonia as a byproduct of amino acid catabolism (109). Indeed, A. baumannii cannot solely grow on sugars and mostly uses amino acids as a carbon source (110). The catabolism of amino acids results in the release of ammonia, with the subsequent alkalization of the extracellular milieu, which is essential for ACV formation in macrophages (109, 111, 112). Within ACVs, A. baumannii deploys additional strategies to counter host-imposed stresses, including activation of stress response pathways, metabolic reprogramming (e.g., PAA catabolism), shifts in carbon source utilization, and surface remodeling (89). For instance, overproduction of LpsB, an enzyme involved in LOS biosynthesis, decreases sensitivity to vancomycin, suggesting enhanced envelope integrity (89). The type I secretion system (T1SS) may also contribute to intracellular survival and replication (106). Transfer of bronchoalveolar lavage fluid containing infected host cells into naïve mice results in productive lung infection, indicating that intracellular A. baumannii remains viable and infectious. These findings suggest that intracellular reservoirs may contribute to persistence, immune evasion, and antibiotic tolerance, potentially leading to treatment failure (89). Interestingly, intracellular strategies vary by cell type. In endothelial cells, the invasive strain ABC141 does not neutralize vacuolar pH via ammonia production. Instead, intracellular replication depends on T1SS, while the type II secretion system (T2SS) is required for host cell invasion (113). In the urinary tract, A. baumannii can also form intracellular reservoirs within bladder epithelial cells (ABIRs), which persist after apparent infection clearance. Reinsertion of a sterile catheter can trigger recurrent infection seeded from these reservoirs (114). Although this facultative intracellular lifestyle has not been demonstrated across all A. baumannii strains (107, 109), its occurrence in diverse cellular and infection models suggests that it may have a significant impact on infection dynamics, persistence, and treatment outcomes.

Plasmid-chromosome crosstalk

Many A. baumannii strains harbor one or more plasmids, which are well known for carrying antibiotic resistance determinants. The rapid expansion of antimicrobial resistance is reflected in the evolution of the large conjugative plasmid pAB3, initially carrying a single resistance cassette in strain ATCC17978, into pAB04, which now contains multiple resistance determinants (37, 69).

Beyond resistance, plasmids play a broader role in regulating bacterial physiology, competitiveness, and virulence. For example, large conjugative plasmids (LCPs) have been shown to repress the type VI secretion system (T6SS), which in A. baumannii primarily mediates interbacterial competition (37). More recent studies further demonstrate that plasmids can influence both virulence and niche adaptation. In the clinical strain UPAB1, the presence of its LCP pAB5 enhances virulence in a catheter-associated urinary tract infection (CAUTI) model, whereas plasmid loss increases virulence in an acute pneumonia model (115). Plasmids also impact intracellular survival. In macrophages, the UPAB1 strain harboring pAB5 can replicate intracellularly, while its plasmid-cured counterpart is rapidly cleared (106). Another example of plasmid-chromosome crosstalk is the regulation of phase switching between the aforementioned virulent-opaque and avirulent-translucent states by the sRNA SrvS, which is encoded on the largest plasmid of AB5075, p1AB5075. SrvS not only regulates the switch frequency, but also which TetR-family transcriptional regulators mediate the switch.

Together, these findings highlight the intricate genetic and regulatory interplay between plasmids and the chromosome in shaping A. baumannii pathogenesis.

CURRENT/FUTURE QUESTIONS

A. baumannii has evolved from an overlooked opportunistic pathogen into a globally significant multidrug-resistant threat. Yet, much of our current understanding still relies on a limited number of laboratory-adapted strains maintained for decades. While strains such as ATCC 19606 and ATCC 17978 have been instrumental, they do not capture the diversity of contemporary clinical isolates. The study of recent strains has already uncovered key traits, including phase variation and an intracellular lifestyle (48, 82, 106, 107), underscoring the need to systematically expand investigations beyond historical models.

Advancing our understanding of A. baumannii pathogenesis also relies on the development of relevant animal models. Widely used infection models, particularly acute murine sepsis and pneumonia (116, 117), have provided critical insights but incompletely reflect the chronic and often polymicrobial nature of A. baumannii infections. Alternative models, including wound, soft tissue, and catheter-associated urinary tract infection (CAUTI) systems (115, 118), as well as more recent chronic pneumonia models enabling sustained infection at clinically relevant inocula (119), offer improved frameworks to study host-pathogen interactions in chronic infections, antibiotic efficacy, and polymicrobial infections. This is particularly relevant given that polymicrobial infections may account for ~25% of A. baumannii cases (120).

A major conceptual advance in recent years is the recognition of A. baumannii as a facultative intracellular pathogen. Evidence from multiple models indicates that the bacterium can establish intracellular populations within host cells, including transient reservoirs in the lung and persistent reservoirs in bladder epithelial cells (ABIRs), capable of reseeding infection following catheter insertion (89, 114). These findings provide a plausible mechanistic basis for clinical observations, including prolonged hospital stays (∼30 days on average) and frequent treatment failure despite in vitro susceptibility (20, 21). However, the extent to which intracellular persistence contributes to human infection remains to be determined. This intracellular lifestyle should be considered when assessing treatment options and represents a key priority for future research.

These findings also raise questions about the origin of infecting strains and the role of host colonization. Specifically, the gastrointestinal tract has emerged as a major determinant of infection risk. Early work identified the gut as a reservoir (121), and more recent studies report colonization rates of up to 40% in hospitalized patients, with a high prevalence at ICU admission (122). Importantly, prior colonization is associated with a markedly increased risk of infection, up to 15-fold higher ([123, 124], reviewed in reference 125). Interestingly, age and feeding practices may also influence gut colonization, as healthy 4-month-old infants fed formula were reported to have a higher prevalence of A. baumannii than breastfed infants (126). Given the clear association between intestinal carriage and increased risk of A. baumannii infection, further investigation of the mechanisms underlying gut colonization and its contribution to disease is warranted. The recent development of a murine model to study A. baumannii gut colonization should provide an important tool for advancing this field (126). Together, these observations highlight the importance of colonization dynamics in both pathogenesis and transmission.

Given the limited therapeutic options available and in line with World Health Organization priorities, significant efforts are being made to develop alternative treatment strategies. Bacteriophage therapy has shown promising results against CRAB in vitro, in animal models, and in clinical case studies (127–131). Phage cocktails can broaden host range, particularly relevant given capsule diversity, and reduce resistance emergence, while also displaying anti-biofilm activity (79, 131). In addition, phage-antibiotic combinations can restore susceptibility to drugs such as ceftazidime and produce synergistic effects ([132–134], reviewed in reference 135).

Complementary approaches based on drug repurposing and antibiotic combinations offer more immediate translational potential. For instance, the non-steroidal anti-inflammatory drug (NSAID) diclofenac enhances A. baumannii susceptibility to colistin in vitro and in vivo (136–138), while various antibiotic combinations have demonstrated synergistic activity (139, 140). Although promising, these strategies require further validation in clinically relevant settings. Preventive strategies remain challenging, particularly due to the highly immunocompromised status of many affected patients. Nonetheless, passive immunization approaches have demonstrated protective effects in animal models, supporting the potential of antibody-based interventions (141–143).

Collectively, these findings reinforce a central paradigm: the success of A. baumannii is not driven by an extensive repertoire of classical virulence factors, but by its exceptional adaptability. Rather than relying on potent toxins or complex secretion systems, it deploys a versatile arsenal of stress response mechanisms that enable it to withstand environmental challenges, reprogram metabolism, and exploit diverse host niches, thereby supporting persistence across clinical settings. Understanding the basis of this adaptability will be essential for developing effective strategies to combat this resilient and minimalist pathogen.

ACKNOWLEDGMENTS

This work was supported by NIH funding to M.F.F. (R01AI166359 and R21AI181334).

Contributor Information

Manon Janet-Maitre, Email: manon.janet-maitre@uni-wuerzburg.de.

Mario F. Feldman, Email: mariofeldman@wustl.edu.

George O'Toole, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire, USA.

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