**1. Introduction**

The global rise of antibiotic resistance in pathogens represents a serious threat to medicine, as it is the predominant cause of treatment failure and increased mortality [1]. Recent evidence suggests that sublethal concentrations of antimicrobials frequently found in the human body and nature play an important role in the development of antibiotic resistance [2]. Initially, susceptible bacterial populations survive and propagate under such conditions due to adaptive gene expression responses that have been observed in a variety of bacterial species [1,3–5]. In Gram-negative bacteria, altering the gene expression of outer membrane proteins or porins, resulting in decreased membrane permeability, is considered one of the first defense mechanisms of adaptation to antibiotic stress [1].

*Yersinia pseudotuberculosis*, a Gram-negative bacterium belonging to the *Enterobacteriaceae* family, is a human pathogen causing pseudotuberculosis infection. In Russia and Japan, it causes outbreaks of the disease known as Far Eastern scarlet-like fever (FESLF), with serious systemic inflammatory symptoms [6].

*Y. pseudotuberculosis* produces two major nonspecific porins, OmpF and OmpC, which we study intensively [7–11]. These porins consist of 16-stranded β-barrel trimers, each of which forms a central channel [12]. The channels control the permeability of the cell envelope for low molecular compounds, including β-lactam, tetracycline, chloramphenicol, and fluoroquinolone antibiotics [13–16]. Thus, the porins provide cell defense against certain antibiotics and subsequently mediate antimicrobial resistance by downregulating their

**Citation:** Bystritskaya, E.; Chernysheva, N.; Stenkova, A.; Guzev, K.; Rakin, A.; Isaeva, M. Differential Expression of *Yersinia pseudotuberculosis* General Porin Genes during Short- and Long-Term Antibiotic Stresses. *Molecules* **2021**, *26*, 3956. https://doi.org/10.3390/ molecules26133956

Academic Editor: Mark Brönstrup

Received: 2 June 2021 Accepted: 23 June 2021 Published: 28 June 2021

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gene expression or inducing beneficial mutations [17]. Moreover, the reversible phenotypical response offers advantages over conventional irreversible mutations [18]. Furthermore, transcriptional porin regulation is considered a rapid adaptive mechanism to environmental and antibiotic stresses occurring within the first 60 min [19]. The porin-mediated stress response has been widely studied in various enterobacteria, including *Escherichia coli*, *Klebsiella pneumonia*, *Salmonella enterica*, *Serratia marcescens*, and others [20–22]. Still, little is known about the effect of antibiotic stress on the general porin regulation in *Y. pseudotuberculosis*. Most research focuses on the effect of lethal antibiotic concentrations on bacterial physiology and resistance, while subinhibitory antimicrobial doses have been mostly disregarded [23]. *Y. pseudotuberculosis* genetic response to low concentrations of antibiotics is of particular interest because successful treatment of pseudotuberculosis infection largely depends on antibiotic therapy to maintain lethal drug concentrations in different human tissues.

Therefore, we aim to investigate the role of general porin regulation in *Y. pseudotuberculosis* adaptation to sublethal concentrations of four antibiotics utilizing porin channels for cell entrance.
