The growing incidence of multidrug-resistant (MDR) or extensively-drug resistant (XDR) bacteria is an emerging challenge in modern medicine. Constant selection of drug-resistant pathogens significantly contributes to the successive reduction of available therapeutic options. MDR and XDR pathogens are frequently resistant to almost all antibiotics, thus significantly limiting available treatment options. These pathogens have been recognized by CDC, as serious threats to human health with mortality rates in invasive infections due to these pathogens, that can exceed 50%. Occurrence of MDR/XDR pathogens considerably reduces the opportunities for effective prophylactics and treatment of infectious diseases. Another vital epidemiological problem is the emergence and spread of novel mechanisms of antimicrobial drug resistance, especially among subpopulations of pathogens persisting in hospital environments. The prevalence of those highly resistant microorganisms contributes significantly to prolonged hospitalization and increased mortality. The growing prevalence of pathogens resistant to most or even all currently available antimicrobial agents heralds the potential risk of a future “post-antibiotic era”.

The enormous genome plasticity of Gram-negative bacteria enables the accumulation of many different mechanisms of resistance to various crucial antimicrobial agents. As a result, the increased emergence of MDR or XDR pathogens considerably reduces the opportunities for effective treatments against these bacteria. The process of bacterial evolution accelerates, primarily due to horizontal gene transfer, a phenomenon which substantially affects the resilience of the bacterial genomes, and consequently influences their outstanding adaptive capacity. An extraordinarily rich gene reservoir, as well as, different mechanisms of bacterial adaptation provides the ability to dynamically respond to various environmental stimuli, such as antimicrobial therapy. A part of multidrug-resistant pathogens tends to integrate many groups of antimicrobial agents, which in extreme cases can lead to the development of the XDR (extensively-drug-resistance) or even PDR (pan-drug-resistance) phenotype. Antimicrobial agents such carbapenems, tigecycline, polymyxins and fosfomycin are currently considered as “last-resort” drugs for therapy of infections caused by MDR/XDR Gram-negative pathogens.

With this Research Topic, we would like to provide an most recent insight on the molecular mechanisms of resistance to "last resort" antimicrobials in Enterobacterales, frequently causing life-threatening infections in the most vulnerable patient populations. This Research Topic is intended to compose a collection of high-quality Original Research articles, Reviews, Mini-Reviews, and Perspective articles that cover, but are not limited to the following themes:

- molecular mechanisms of resistance to “last resort” antimicrobials
- characterization of mobile genetic elements (MGEs) involved in dissemination of factors involved in resistance to “last resort” antimicrobials
- description of bacterial regulatory mechanisms involved in resistance to “last resort” antimicrobials
- molecular epidemiology of Enterobacterales resistant to "last resort" antimicrobials
- perspective on available therapeutic options

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Molecular mechanisms of resistance to "last resort" antimicrobials in Enterobacterales Volume II