Molecular mechanisms of tigecycline-resistance among Enterobacterales

Abstract

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.

Keywords: Enterobacterales; efflux pumps; glycylcyclines; multidrug resistance (MDR); tigecycline.

Figure 1

Timeline of tigecycline (Yaghoubi et al., 2022). Figure exhibits a timeline from first approval of tetracycline to the launch of tigecycline in China. Before tigecycline use in China there were reported resistant Acinetobacter strains.

Figure 2

Groups of hazards according to CDC report (the most crucial microorganisms) (CDC, 2019). CDC divided pathogens in the four groups of hazards. In serious threats and urgent threats there are Enterobacterales and their representatives, primarily carbapenem-resistant Enterobacterales.

Figure 3

Frequent mechanisms of resistance are present in gram-negative strains (Sharma et al., 2019).

Figure 4

Mechanisms of efflux pumps (Sharma et al., 2019). MacAB-TolC pump consists of three elements: MacB and TolC, which extrude toxic substances, the MacA-MacB linkage and TolC. MacAB-TolC is an ATP-dependent pump. AcrAB-TolC pump is a representative of the RND family, consisting of three parts: AcrB and TolC, extruding harmful substances, AcrA, which links AcrB, and TolC. AcrAB-TolC efflux pump is a proton-motive force-dependent efflux pump.