Resistance mechanisms of tigecycline in Acinetobacter baumannii

Abstract

Acinetobacter baumannii is widely distributed in nature and in hospital settings and is a common pathogen causing various infectious diseases. Currently, the drug resistance rate of A. baumannii has been persistently high, showing a worryingly high resistance rate to various antibiotics commonly used in clinical practice, which greatly limits antibiotic treatment options. Tigecycline and polymyxins show rapid and effective bactericidal activity against CRAB, and they are both widely considered to be the last clinical line of defense against multidrug resistant A. baumannii. This review focuses with interest on the mechanisms of tigecycline resistance in A. baumannii. With the explosive increase in the incidence of tigecycline-resistant A. baumannii, controlling and treating such resistance events has been considered a global challenge. Accordingly, there is a need to systematically investigate the mechanisms of tigecycline resistance in A. baumannii. Currently, the resistance mechanism of A. baumannii to tigecycline is complex and not completely clear. This article reviews the proposed resistance mechanisms of A. baumannii to tigecycline, with a view to providing references for the rational clinical application of tigecycline and the development of new candidate antibiotics.

Exploring non-toxic co-evolutionary docking

“…All these would had been impossible for any other more "traditional" computational screening (i.e., AutoDockVina, Yasara, seeSAR, etc) of largest chemical libraries (i.e., Mcule, ChemSpace, Zinc, PubChem, Chembl, etc) which would have required much more computational time. On the other hand, most actual machine-learning approaches to docking 91,92 ; including those employing the new transformer methods 78,91,[93][94][95] , are actually limited in their accuracies because of the reduced numbers of examples of small-drugs protein interactions required for model training 96 . Some hands-on experience of the state-of-the-art of machine-learning trained models, was acquired by employing Hots proposed methods 91 Hots predicted both docking-cavities and ligand docking-scores solely from protein amino acid sequences 91 .…”

Unveiling the Secrets of Acinetobacter baumannii: Resistance, Current Treatments, and Future Innovations

“…The AdeABC efflux pump consists of three proteins: AdeA, AdeB, and AdeC. AdeB is a critical component, serving as the multi-drug transporter, while AdeA and AdeC facilitate the process by forming a structural complex that supports the function of AdeB [51]. Regulation of this efflux pump is intricately controlled by genetic elements and regulatory systems.…”

“…Specific mutations in AdeRS, like A94V and S8A in AdeS or P56S in AdeR, are known to upregulate AdeABC expression, thereby increasing resistance to tigecycline. Moreover, the insertion of genetic elements such as IS Aba1 into the adeS gene has been proven to elevate adeB expression, further enhancing efflux activity and resistance [51]. Additionally, environmental pressures, such as exposure to sub-minimal inhibitory concentrations (sub-MIC) of tigecycline, can induce adaptive changes.…”

Portrait of a killer: Uncovering resistance mechanisms and global spread of Acinetobacter baumannii

“…For example, the adeABC operon encodes AdeA (membrane fusion protein), AdeB (multidrug transporter), and AdeC (outer membrane protein) to form a pump spanning the inner and outer membrane (Fig 2A ), and its expression is regulated by the AdeRS TCS in response to fluoroquinolone exposure (Fig 2) [41]. However, constitutive overexpression of adeABC results in broader resistance (to aminoglycosides, tetracyclines, chloramphenicol, β-lactams, and tigecycline) and can occur as a result of ISAba1 insertion upstream of adeABC (Fig 2B ) or via point mutations in adeR or adeS, having major clinical implications [42][43][44]. Interestingly, inherent efflux activity seems to act in a strain-dependent context, where certain pumps are expressed in different strains; for example, AdeABC appears to be more active in ATCC17978, whereas AdeIJK is more active in AB5075 (GC1) for drug resistance [40,45].…”