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Microorganisms
Special Issues
The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria
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The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (30 April 2026) | Viewed by 4372

Special Issue Editors

Dr. Ewa Laskowska

E-Mail Website
Guest Editor
Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdańsk, Poland
Interests: bacterial physiology; biofilm; bacterial stress responses; heat shock proteins; antibiotic tolerance
Dr. Arumugam Priya

E-Mail Website
Guest Editor Assistant
Department of Medicine, Division of Gastroenterology and Hepatology, Pennsylvania State University College of Medicine, Hershey, PA, USA
Interests: biofilms; strategies to combat antimicrobial resistance; inflammatory bowel disease and tight junction

Special Issue Information

Dear Colleagues,

Bacteria combat an array of stresses in their natural setting, which elicit a variety of adaptive responses as a survival mechanism. Effective adaptive response ensues in bacterial persistence, antibiotic resistance, biofilm formation and resistance development. Understanding the intricacy of mechanisms governing the adaptation can support the advancement of suitable antimicrobials. This Special Issue brings together the cutting-edge research studies exploring the molecular mechanisms in bacterial stress adaptation, emphasizing signal transduction pathways, transcriptional and translational regulations, metabolic reprogramming, etc.

Key topics include two component regulatory systems, toxin–antitoxin systems and small regulatory RNAs in coordinating stress response. We also feature insights on bacterial persistence strategies, such as biofilm formation and virulence development and their implications on antibiotic resistance and pathogenesis. By elucidating these mechanisms, this collection aims to expand our knowledge about bacterial resilience and inform novel antimicrobial strategies.

We invite researchers to contribute to this Special Issue, which offers to impart recent discoveries in bacterial stress adaptation and promote new avenues in infectious disease research.

Dr. Ewa Laskowska
Guest Editor

Dr. Arumugam Priya
Guest Editor Assistant

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biofilms
  • strategies to combat antimicrobial resistance
  • bacterial stress adaptation

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Published Papers (5 papers)

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Research

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13 pages, 3733 KB  
Article
Functional Characterization of the Histidine Kinase BaeS Reveals Critical Residues for BaeSR-Dependent Stress Signaling in Escherichia coli
by Shurong Chen, Zhengfei Qi, Lina Wang, Lian Wu, Jiayi Xie, Rui Ma, Kexin Zhang, Tong Ji, Min Zhou, Lingli Zheng and Qingshan Bill Fu
Microorganisms 2026, 14(5), 1031; https://doi.org/10.3390/microorganisms14051031 - 1 May 2026
Abstract
Escherichia coli, a facultative anaerobic Gram-negative member of the Enterobacteriaceae, is an increasingly important opportunistic pathogen driven in part by rising resistance to clinically important antibiotics. Regulation of multidrug efflux systems by two-component signal transduction pathways, particularly the BaeSR system, plays a [...] Read more.
Escherichia coli, a facultative anaerobic Gram-negative member of the Enterobacteriaceae, is an increasingly important opportunistic pathogen driven in part by rising resistance to clinically important antibiotics. Regulation of multidrug efflux systems by two-component signal transduction pathways, particularly the BaeSR system, plays a central role in this process. However, the functional residues governing signal transduction through the sensor kinase BaeS remain incompletely defined. In this study, we integrated domain prediction, homology-guided site-directed mutagenesis, in vitro protein purification, autophosphorylation assays, and reverse-transcription quantitative polymerase chain reaction (RT-qPCR)-based transcriptional analysis of selected BaeSR-regulated genes to delineate key residues required for BaeS function. Sequence analysis identified His250 as a candidate autophosphorylation site and Asn364 as a conserved residue within the catalytic domain. Biochemical characterization of purified wild-type BaeS and an H250A mutant demonstrated that His250 is indispensable for autophosphorylation. Consistently, RT-qPCR analysis showed that BaeS activation markedly induced the transcription of BaeSR-regulated efflux-associated genes, whereas genetic deletion of baeS or selective disruption of kinase activity by the N364A mutation abolished this response. Together, these findings establish His250 as a key residue for BaeS autophosphorylation and identify Asn364 as essential for inducible BaeSR signaling and activation of resistance-associated target genes, thereby establishing an experimental framework for elucidating BaeSR-mediated efflux regulation and informing future studies of resistance regulatory networks and potential intervention strategies centered on key signaling nodes. Full article
(This article belongs to the Special Issue The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria)
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14 pages, 3241 KB  
Article
Recombinant Cytosolic Truncations of Histidine Kinases Retain Function for Targeted In Vitro Investigations
by Jude Kinkead, Alexander D. Hondros, Aimee M. Figg, Milah M. Young, Richele J. Thompson, Christian Melander and John Cavanagh
Microorganisms 2026, 14(2), 510; https://doi.org/10.3390/microorganisms14020510 - 22 Feb 2026
Viewed by 475
Abstract
Histidine kinases are an integral component of bacterial two-component systems (TCSs), playing a pivotal role in signal transduction pathways, resulting in both resistance and virulence. However, their inherent membrane-bound nature often results in poor solubility, making them difficult to isolate and rendering them [...] Read more.
Histidine kinases are an integral component of bacterial two-component systems (TCSs), playing a pivotal role in signal transduction pathways, resulting in both resistance and virulence. However, their inherent membrane-bound nature often results in poor solubility, making them difficult to isolate and rendering them incompatible with most in vitro biochemical techniques. Consequently, much of the research on two-component systems has centered on response regulators, limiting both drug discovery efforts and our broader understanding of key signal transduction mechanisms. To address these challenges, we sought to straightforwardly generate cytosolic truncation mutants of histidine kinases that retain their autophosphorylation and phosphotransfer capabilities. Previously, we successfully developed a cytosolic truncation mutant of PmrB (PmrBc) that maintained these critical functions, demonstrating its suitability as a viable surrogate for in vitro investigations, including inhibitor compound screening. Building upon this foundation, we have refined our methods and here demonstrate these improvements by producing functional histidine kinase truncation mutants from the following diverse bacterial species: Escherichia coli; PhoQ, BasS and Klebsiella pneumoniae; and PmrB and PhoQ. Full article
(This article belongs to the Special Issue The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria)
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18 pages, 3040 KB  
Article
PmrA Mutations in Drug-Resistant Acinetobacter baumannii Affect Sensor Kinase-Response Regulator Interaction and Phosphotransfer
by Felicia E. Jaimes, Alexander D. Hondros, Jude Kinkead, Morgan E. Milton, Richele J. Thompson, Aimee M. Figg, Christian Melander and John Cavanagh
Microorganisms 2025, 13(11), 2600; https://doi.org/10.3390/microorganisms13112600 - 15 Nov 2025
Cited by 2 | Viewed by 912
Abstract
Multi-drug resistance in Acinetobacter baumannii poses a significant human health threat. For multidrug-resistant pathogens, ‘last line of defense’ antibiotics like the polymyxins are implemented. Concerningly, polymyxin-resistance is evidenced in Acinetobacter baumannii and is mediated by the PmrAB two-component system. The response regulator PmrA [...] Read more.
Multi-drug resistance in Acinetobacter baumannii poses a significant human health threat. For multidrug-resistant pathogens, ‘last line of defense’ antibiotics like the polymyxins are implemented. Concerningly, polymyxin-resistance is evidenced in Acinetobacter baumannii and is mediated by the PmrAB two-component system. The response regulator PmrA upregulates pmrC, leading to lipooligosaccharide modifications that reduce polymyxin binding. Sequencing of A. baumannii resistant isolates has identified point mutations in the receiver domain of PmrA that correlate with increased resistance. To investigate functional impacts of these mutations, we characterized five PmrA mutations (D10N, M12I, I13M, G54E, and S119T) by assessing changes in PmrA DNA-binding affinity, dimerization, phosphorylation, and structure. Our findings suggest that these mutations impact the ability of PmrA to receive the activating phosphoryl group from the sensor kinase PmrB. The slow phosphoryl uptake is likely due to (1) disruption of the PmrB-PmrA interaction by interfering with the recognition site on PmrA, or (2) perturbation of PmrA’s active site via steric hindrance or displacement of residues and ions necessary for coordination within the aspartic acid pocket. Slowed phosphorylation of a response regulator can lead to enhanced gene transcription through several mechanisms. These insights advance our understanding of PmrA-mediated resistance in A. baumannii. Full article
(This article belongs to the Special Issue The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria)
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15 pages, 4058 KB  
Article
SpuA-Mediated Glycogen Metabolism Modulates Acid Stress Adaptation via Formic Acid and Amino Acid Utilization in Streptococcus pneumoniae
by Weichen Gong, Masayuki Ono, Xuefei Cheng, Yujiro Hirose, Keita Nishiyama, Haruki Kitazawa and Shigetada Kawabata
Microorganisms 2025, 13(10), 2409; https://doi.org/10.3390/microorganisms13102409 - 21 Oct 2025
Cited by 1 | Viewed by 915
Abstract
Glycogen metabolism plays a key role in bacterial adaptation. In Streptococcus pneumoniae, the glycogen-degrading enzyme SpuA is widely conserved, but its physiological significance remains unclear. In this study, we investigated how SpuA affects bacterial growth and response to acid stress. We found [...] Read more.
Glycogen metabolism plays a key role in bacterial adaptation. In Streptococcus pneumoniae, the glycogen-degrading enzyme SpuA is widely conserved, but its physiological significance remains unclear. In this study, we investigated how SpuA affects bacterial growth and response to acid stress. We found that the spuA deletion strain (ΔspuA) produced more acidic metabolites under anaerobic conditions than the wild-type strain. In a mouse infection model, bronchoalveolar lavage fluid (BALF) from ΔspuA-infected mice was more acidic on day 1 post-infection, showing a lower bacterial load than wild-type infection—a finding consistent with the early growth delay observed in vitro—but the mutant later exhibited enhanced persistence at 72 h. ΔspuA strains also showed greater tolerance to formic acid and higher intake of serum amyloid A1 (SAA1), which may further contribute to their survival in acidic environments. Transcriptomic analysis revealed reduced utilization of certain amino acids, particularly cysteine, in ΔspuA strains. However, the addition of 0.05% (v/v) formic acid restored amino acid utilization in ΔspuA strains, and co-supplementation with formic acid and cysteine significantly enhanced ΔspuA growth in vitro. These findings suggest that in the absence of SpuA, S. pneumoniae shifts its metabolism toward formic acid production, which may act both as a metabolic signal and a stressor that influences bacterial gene expression. This shift is accompanied by increased expression of tRNAs and growth rescue, suggesting enhanced amino acid utilization capacity. Although our findings reveal a potential link between formic acid metabolism and amino acid utilization through tRNA regulation, further validation using metabolic flux analyses or targeted metabolomics will be required to confirm this relationship. These observations imply a metabolic adaptation that facilitates bacterial growth under low-oxygen, acidic conditions during infection. Our results also raise the possibility that SpuA plays a role in restraining bacterial overgrowth in the host, thereby promoting a more balanced coexistence between pathogen and host. Full article
(This article belongs to the Special Issue The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria)
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Review

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18 pages, 1333 KB  
Review
Bacterial Adaptation to Stress Induced by Glyoxal/Methylglyoxal and Advanced Glycation End Products
by Dorota Kuczyńska-Wiśnik, Karolina Stojowska-Swędrzyńska and Ewa Laskowska
Microorganisms 2025, 13(12), 2778; https://doi.org/10.3390/microorganisms13122778 - 6 Dec 2025
Cited by 1 | Viewed by 1516
Abstract
Glyoxal (GO) and methylglyoxal (MGO) are highly toxic metabolic byproducts that induce carbonyl stress in bacteria and eukaryotes. Their accumulation in cells is linked to non-enzymatic glycosylation (glycation) of proteins, nucleic acids, and lipids, leading to the formation of advanced glycation end products [...] Read more.
Glyoxal (GO) and methylglyoxal (MGO) are highly toxic metabolic byproducts that induce carbonyl stress in bacteria and eukaryotes. Their accumulation in cells is linked to non-enzymatic glycosylation (glycation) of proteins, nucleic acids, and lipids, leading to the formation of advanced glycation end products (AGEs). In humans, AGEs are associated with several health problems, such as diabetes, Alzheimer’s disease, cancer, and aging. Recent studies indicate that, despite their short lifespan, bacteria are also affected by AGEs formation. In this review, we summarize the pathways and mechanisms that help bacteria cope with GO, MGO, and AGEs. We also discuss the impact of dietary AGEs on gut microbiota and the antibacterial activity of host-derived GO/MGO. Recent studies highlight three main areas for future research: the role of AGEs in dysbiosis, the regulation of protein activities by MGO/GO-dependent modifications, and the potential use of glyoxalase pathway inhibitors to combat pathogens. This last point is especially important due to the rising prevalence of multidrug-resistant strains and the failure of antibiotic therapies. Full article
(This article belongs to the Special Issue The Molecular Mechanisms Regulating Stress-Adaptive Responses in Bacteria)
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