Carbapenem Resistance in Acinetobacter baumannii: Mechanisms, Therapeutics, and Innovations

Abstract

The global rise of carbapenem-resistant Acinetobacter baumannii (CRAB) strains poses a critical challenge to healthcare systems due to limited therapeutic options and high mortality rates, especially in intensive care settings. This review explores the epidemiological landscape and molecular mechanisms driving carbapenem resistance, including the production of diverse beta-lactamases (particularly OXA-type enzymes), porin loss, efflux pump overexpression, and mutations in antibiotic targets. Emerging treatment strategies are discussed, such as the use of new beta-lactam-beta-lactamase inhibitor combinations (e.g., sulbactam-durlobactam), siderophore cephalosporins, next-generation polymyxins, as well as novel agents like zosurabalpin and rifabutin (BV100). Alternative approaches-including phage therapy, antimicrobial peptides, CRISPR-based gene editing, and nanoparticle-based delivery systems-are also evaluated for their potential to bypass traditional resistance mechanisms. Furthermore, advances in artificial intelligence and multi-omics integration are highlighted as tools for identifying novel drug targets and predicting resistance profiles. Together, these innovations represent a multifaceted strategy to overcome CRAB infections, yet their successful implementation requires further clinical validation and coordinated surveillance efforts. This analysis highlights the urgent need for continued investment in innovative treatments and effective resistance monitoring to limit the spread of CRAB and protect the effectiveness of last-line antibiotics.

Keywords: Acinetobacter baumannii; alternative therapies; antimicrobial peptides; artificial intelligence; beta-lactamases; carbapenem resistance; efflux pumps; phage therapy.

Figure 1

The timeline of key publications related to carbapenem resistance in A. baumannii. The figure highlights the first reports of major carbapenemases being identified in A. baumannii and the evolution of the species into a globally recognised critical pathogen. Abbreviations: CRAB, carbapenem-resistant Acinetobacter baumannii; MDR, multidrug-resistant; ESKAPE, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli; WHO, World Health Organisation. References corresponding to events in the timeline: 1986 [4]; 1990s [3]; 1993 [5]; 2000 [6]; 2003 [7]; 2004 [8]; 2005 [9]; 2008 [10]; 2009 [11]; 2010 [12]; 2013 [13]; 2017 [14]; 2024 [15].

Figure 2

Schematic representation of the main mechanisms underlying carbapenem resistance in A. baumannii. * The bla_OXA-51 gene is intrinsic to A. baumannii and has limited carbapenemase activity, but its expression increases significantly when associated with upstream IS elements. ** Among the class C β-lactamases identified in A. baumannii, ADC-68 is, to date, the only variant experimentally confirmed to possess carbapenemase activity.

Figure 3

Integration of therapeutic and investigative strategies for CRAB through innovative and computational approaches. Abbreviation: AMP, antimicrobial peptides.