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Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due to drug resistance, and opportunities for infection turned it into one of the most important threats to human health. Some of the clinical manifestations of A. baumannii nosocomial infection are pneumonia; bloodstream infections; lower respiratory tract, urinary tract, and wound infections; burn infections; skin and soft tissue infections (including necrotizing fasciitis); meningitis; osteomyelitis; and endocarditis. A. baumannii has an extraordinary genetic plasticity that results in a high capacity to acquire antimicrobial resistance traits. In particular, acquisition of resistance to carbapenems, which are among the antimicrobials of last resort for treatment of multidrug infections, is increasing among A. baumannii strains compounding the problem of nosocomial infections caused by this pathogen. It is not uncommon to find multidrug-resistant (MDR, resistance to at least three classes of antimicrobials), extensively drug-resistant (XDR, MDR plus resistance to carbapenems), and pan-drug-resistant (PDR, XDR plus resistance to polymyxins) nosocomial isolates that are hard to treat with the currently available drugs. In this article we review the acquired resistance to carbapenems by A. baumannii. We describe the enzymes within the OXA, NDM, VIM, IMP, and KPC groups of carbapenemases and the coding genes found in A. baumannii clinical isolates.

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections 1 , 2 . The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin 3 . Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1 -mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae , which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens 4 . In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens. The discovery and synthesis of a colistin congener provide a promising clinical lead against mcr-1 -encoding colistin-resistant pathogens, which are responsible for an increasing number of deaths from antibiotic-resistant infections.

A new phenotypic test, called the Carbapenem Inactivation Method (CIM), was developed to detect carbapenemase activity in Gram-negative rods within eight hours. This method showed high concordance with results obtained by PCR to detect genes coding for the carbapenemases KPC, NDM, OXA-48, VIM, IMP and OXA-23. It allows reliable detection of carbapenemase activity encoded by various genes in species of Enterobacteriaceae (e.g., Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae), but also in non-fermenters Pseudomonas aeruginosa and Acinetobacter baumannii. The CIM was shown to be a cost-effective and highly robust phenotypic screening method that can reliably detect carbapenemase activity.

The global emergence of Acinetobacter baumannii is of great concern, especially inside intensive care units (ICUs). This study investigated the prevalence, antibiotic resistance, biofilm formation and genetic relatedness of A. baumannii recovered from ICU patients in three major hospitals in Jordan. The A. baumannii isolates included in this study were identified by the detection of the blaOXA-51 gene, and a multiplex PCR assay. Antibiotic susceptibility testing was performed using the disk diffusion and broth microdilution methods, and the ability of the isolates to form biofilms was tested using the 96-well plate assay. All isolates were tested for the presence of carbapenemases-encoding genes by PCR. Clonal relatedness was assessed by Rep-PCR and dendrogram analysis. Overall, 148 A. baumannii isolates were identified, with 96.7% of the isolates recognized as carbapenem resistant A. baumannii. Based on their resistance patterns, 90% of the isolates were extensively resistant (XDR). The highest prevalence of carbapenemases-encoding genes was for blaOXA-23-like (96.7%), followed by blaADC (93.9.2%), blaVIM (56.8%) and blaNDM-1 (7.4%). Almost 80% of the isolates were able to form biofilms, with 63.2% classified as strong biofilm former. Rep-PCR and clustering analysis revealed 26 different clusters and the circulation of hospital-specific clones. Our study revealed an alarming high prevalence of XDR, blaOXA-23-carrying and strong biofilm-producing A. baumannii among ICU patients. These findings call for continuous epidemiological surveillance and implementation of prevention strategies to reduce infections and dissemination of such a problematic pathogen inside the ICUs.

To colonize and survive in the host, bacterial pathogens like Acinetobacter baumannii must acquire zinc (Zn). To maintain Zn homeostasis, A. baumannii synthesizes proteins of the COG0523 family which are predicted to chaperone Zn to metalloproteins. Bioinformatic tools identified A. baumannii A1S_0934 as a COG0523 protein, and yeast two-hybrid screening revealed that MurD, an essential muramyl ligase, interacts with A1S_0934. As such, we have named A1S_0934 MurD interacting GTPase COG0523 (MigC). Here we show that MigC is a GTPase whose activity is stimulated upon Zn coordination to a characteristic CxCC (C = Cys; x = Leu/Ile/Met) motif to form a S 3 (N/O) complex. MigC-deficient strains (Δ migC ) display sensitivity to Zn depletion and exhibit altered cell wall architecture in vitro . Biochemical and functional assays confirm the MigC-MurD interaction, which inhibits the catalytic activity of MurD. CRISPRi knockdowns of murD reduce A. baumannii fitness and increase filamentation during Zn depletion, a phenotype reversed in Δ migC strains, suggesting that MigC also inhibits MurD activity in cells. Δ migC cells are elongated and sensitized to ceftriaxone, a cephalosporin antibiotic, consistent with decreased cell wall integrity. The Δ migC strain has reduced ability to colonize in a murine model of pneumonia highlighting the importance of the MigC-MurD interaction induced by A. baumannii infection. Together these data suggest that MigC impacts cell wall biogenesis, in part through interactions with MurD, emphasizing the importance of MigC and MurD to the survival and pathogenicity of A. baumannii while expanding the potential functions of the COG0523 family of enzymes.

•In a longitudinal study of carbapenem-resistant Acinetobacter baumannii strains of Portugal conducted (n = 26, 2005–2019), a clear increase in antimicrobial resistance profile was observed over the years, explaining in part the successful dominance of specific clones.•There is a low diversity of capsule types (KL7 > KL2 > KL120 > KL9, ordered by decreasing prevalence), among >120 KL types available in A baumannii, with different virulence.•Correlations between OXA genes with specific sequence type (ST)/KL types were identified (eg, OXA-40-like/ST46Past/KL9 or KL120 and OXA-23-like/ST2Past/KL2).•Clonal shifts of carbapenem-resistant Acinetobacter baumannii (OXA-40-like/ST46 in 2005 and OXA-23-like/ST2 in 2006–2019) were observed. Particular KL shifts (KL2, KL7, and KL9) within ST2 (or clonal complex II) were also found, potentially favoring its adaptation and worldwide global dominance. Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important nosocomial pathogen. The capsular type (K-type) is considered a major virulence factor, contributing to the evasion of host defenses. The global spread and dissemination dynamics between K-types, sequence types (ST), antibiotic resistance genes, and virulence factors remain largely unknown in Portugal. A collection of 96 CRAB clinical samples collected between 2005 and 2019 in the northern region of Portugal were tested for antimicrobial susceptibility profile and screened by polymerase chain reaction for resistance genetic determinants. A subset of 26 representative isolates was subjected to whole-genome sequencing to assess K types, ST types, and genomic relatedness. The pathogenicity of distinct K-types was also tested using Galleria mellonella model. For the 96 CRAB isolates analyzed, high antimicrobial resistance (>90%) was observed to the carbapenems, fluoroquinolones, and miscellaneous agents. Greater antimicrobial susceptibility (∼30%–57%) was observed for aminoglycosides, particularly tobramycin, and amikacin. Genotypically, 75 strains (78.5%) carried blaOXA-23-like, 18 strains (18.8%) carried blaIMP-like, and 11 strains (14.9%) carried blaOXA-40-like carbapenem resistance genes, respectively. Associations between OXA and ST/capsular locus (KL) types were observed over the years (eg, OXA-40-like/ST46Past/KL120 and OXA-23-like/ST2Past/KL2). ST2Past of clonal complex II was present in most strains, a dominant drug-resistant lineage in the United States and Europe. KL7 was also the most prevalent KL-type (38.5%), followed by KL2 (34.6%), KL120 (23.1%), and KL9 (3.8%). Virulence assessment for different K-types in a Galleria mellonella model revealed a significantly increased virulence for KL120 when compared with KL7, KL9, and KL2. There are specific CRAB serotypes circulating in Portugal, accounting by the low diversity of acquired carbapenemase genes (OXA-23-like and OXA-40-like), ST types (ST2 and ST46) and KL types (KL2, KL7, KL9, and KL120) identified. The high prevalent of ST2, especially when associated with KL2 and blaOXA-23-like, suggest that antibiotic resistance has been driven by clonal expansion of clonal complex II. Such findings provide useful information on the diversity of multidrug-resistant bacterium that might be relevant for antibacterial interventions.

The genus Acinetobacter comprises both environmental and clinically relevant species associated with hospital-acquired infections. Among them, Acinetobacter baumannii is a critical priority bacterial pathogen, for which the research and development of new strategies for antimicrobial treatment are urgently needed. Acinetobacter spp. produce a variety of structurally diverse capsular polysaccharides (CPSs), which surround the bacterial cells with a thick protective layer. These surface structures are primary receptors for capsule-specific bacteriophages, that is, phages carrying tailspikes with CPS-depolymerizing/modifying activities. Phage tailspike proteins (TSPs) exhibit hydrolase, lyase, or esterase activities toward the corresponding CPSs of a certain structure. In this study, the data on all lytic capsule-specific phages infecting Acinetobacter spp. with genomes deposited in the NCBI GenBank database by January 2024 were summarized. Among the 149 identified TSPs encoded in the genomes of 143 phages, the capsular specificity (K specificity) of 46 proteins has been experimentally determined or predicted previously. The specificity of 63 TSPs toward CPSs, produced by various Acinetobacter K types, was predicted in this study using a bioinformatic analysis. A comprehensive phylogenetic analysis confirmed the prediction and revealed the possibility of the genetic exchange of gene regions corresponding to the CPS-recognizing/degrading parts of different TSPs between morphologically and taxonomically distant groups of capsule-specific Acinetobacter phages.

Background Acinetobacter baumannii , a Gram-negative member of the ESKAPE pathogen group, is known to develop resistance to several antibiotics rapidly, and carbapenem-resistant A. baumannii (CRAB) is highly implicated in life-threatening infections, especially within hospital settings. Objectives This study detected CRAB in clinical and hospital-environmental samples, evaluated the antibiotic resistance patterns and screened for prevalent carbapenemase genes in isolates from a hospital in Southwest Nigeria. Methods A total of 150 clinical and hospital environmental samples were analysed using culture-dependent and molecular methods for the detection of Acinetobacter baumannii. Antibiotic susceptibility test was done using the Kirby-Bauer disk diffusion technique. Phenotypic screening for carbapenemase was via simplified carbapenem inactivation method (sCIM), and molecular detection of bla KPC type, bla OXA−48−like , bla VIM type, bla NDM−1 , bla IMP variants and bla OXA−23−like genes by Polymerase chain reaction. Results Altogether, only 29.4% (42/143 isolates) of recovered isolates were identified as A. baumannii , giving a prevalence of 28.0% (42/150 samples), predominantly from sputum. All isolates had the gluconolactonase gene, while 5/42 had the bla OXA - 51 - like gene. Resistance to meropenem and cefiderocol was 100.0% and 88.1%, respectively, while gentamicin was most effective in vitro (7.1%); 54.8% were multidrug-resistant, and 88.1% (37/42) had MARI ≥ 0.2. Overall, 39/42 (92.9%) isolates had ≥ one or more carbapenemase genes; 61.9% (26/42) had the bla KPC type gene, 59.5% (25/42) had the bla IMP variants while 45.2% had the bla VIM type gene; no strain had the bla NDM−1 or the bla OXA−23−like gene. Conclusion This study reports the occurrence of MDR strains, and of bla KPC type, bla IMP variants and bla VIM type carbapenemase genes in A. baumannii isolates from clinical and hospital environmental samples, contributing to the pool of existing data on their occurrence. It also highlights the need for monitoring and continued surveillance of the strains, most especially in the clinical setting.

Acinetobacter baumannii is an opportunistic Gram-negative pathogen that causes a wide range of infections including pneumonia, septicemia, necrotizing fasciitis and severe wound and urinary tract infections. Analysis of A. baumannii representative strains grown in Chelex 100-treated medium for hemolytic activity demonstrated that this pathogen is increasingly hemolytic to sheep, human and horse erythrocytes, which interestingly contain increasing amounts of phosphatidylcholine in their membranes. Bioinformatic, genetic and functional analyses of 19 A. baumannii isolates showed that the genomes of each strain contained two phosphatidylcholine-specific phospholipase C (PC-PLC) genes, which were named plc1 and plc2. Accordingly, all of these strains were significantly hemolytic to horse erythrocytes and their culture supernatants tested positive for PC-PLC activity. Further analyses showed that the transcriptional expression of plc1 and plc2 and the production of phospholipase and thus hemolytic activity increased when bacteria were cultured under iron-chelation as compared to iron-rich conditions. Testing of the A. baumannii ATCC 19606T plc1::aph-FRT and plc2::aph isogenic insertion derivatives showed that these mutants had a significantly reduced PC-PLC activity as compared to the parental strain, while testing of plc1::ermAM/plc2::aph demonstrated that this double PC-PLC isogenic mutant expressed significantly reduced cytolytic and hemolytic activity. Interestingly, only plc1 was shown to contribute significantly to A. baumannii virulence using the Galleria mellonella infection model. Taken together, our data demonstrate that both PLC1 and PLC2, which have diverged from a common ancestor, play a concerted role in hemolytic and cytolytic activities; although PLC1 seems to play a more critical role in the virulence of A. baumannii when tested in an invertebrate model. These activities would provide access to intracellular iron stores this pathogen could use during growth in the infected host.

Acinetobacter baumannii , a predominant nosocomial pathogen, represents a grave threat to public health due to its multiple antimicrobial resistance. Managing patients afflicted with severe infections caused by multiple drug-resistant A. baumannii is particularly challenging, given the associated high mortality rates and unfavorable prognoses. The diminishing efficacy of antibiotics against this superbug underscores the urgent necessity for novel treatments or strategies to address this formidable issue. Bacteriophage-derived polysaccharide depolymerase enzymes present a potential approach to combating this pathogen. These enzymes target and degrade the bacterial cell’s exopolysaccharide, capsular polysaccharide, and lipopolysaccharide, thereby disrupting biofilm formation and impairing the bacteria’s defense mechanisms. Nonetheless, the narrow host range of phage depolymerases limits their therapeutic efficacy. Despite the benefits of these enzymes, phage-resistant strains have been identified, highlighting the complexity of phage-host interactions and the need for further investigation. While preliminary findings are encouraging, current investigations are limited, and clinical trials are imperative to advance this treatment approach for broader clinical applications. This review explores the potential of phage-derived depolymerase enzymes against A. baumannii infections.