scholarly journals Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

2019 ◽  
Vol 20 (7) ◽  
pp. 1781 ◽  
Author(s):  
Anjali Y. Bhagirath ◽  
Yanqi Li ◽  
Rakesh Patidar ◽  
Katherine Yerex ◽  
Xiaoxue Ma ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Pathogenic Bacteria ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Gram Negative ◽  
Environmental Signals ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets.

scholarly journals Pangenome Analytics Reveal Two-Component Systems as Conserved Targets in ESKAPEE Pathogens

mSystems ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Akanksha Rajput ◽  
Yara Seif ◽  
Kumari Sonal Choudhary ◽  
Christopher Dalldorf ◽  
Saugat Poudel ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Content Type ◽  
Vital Functions ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

ABSTRACT The two-component system (TCS) helps bacteria sense and respond to environmental stimuli through histidine kinases and response regulators. TCSs are the largest family of multistep signal transduction processes, and they are involved in many important cellular processes such as antibiotic resistance, pathogenicity, quorum sensing, osmotic stress, and biofilms. Here, we perform the first comprehensive study to highlight the role of TCSs as potential drug targets against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli) pathogens through annotation, mapping, pangenomic status, gene orientation, and sequence variation analysis. The distribution of the TCSs is group specific with regard to Gram-positive and Gram-negative bacteria, except for KdpDE. The TCSs among ESKAPEE pathogens form closed pangenomes, except for Pseudomonas aeruginosa. Furthermore, their conserved nature due to closed pangenomes might make them good drug targets. Fitness score analysis suggests that any mutation in some TCSs such as BaeSR, ArcBA, EvgSA, and AtoSC, etc., might be lethal to the cell. Taken together, the results of this pangenomic assessment of TCSs reveal a range of strategies deployed by the ESKAPEE pathogens to manifest pathogenicity and antibiotic resistance. This study further suggests that the conserved features of TCSs might make them an attractive group of potential targets with which to address antibiotic resistance. IMPORTANCE The ESKAPEE pathogens are the leading cause of health care-associated infections worldwide. Two-component systems (TCSs) can be used as effective targets against pathogenic bacteria since they are ubiquitous and manage various vital functions such as antibiotic resistance, virulence, biofilms, quorum sensing, and pH balance, among others. This study provides a comprehensive overview of the pangenomic status of the TCSs among ESKAPEE pathogens. The annotation and pangenomic analysis of TCSs show that they are significantly distributed and conserved among the pathogens, as most of them form closed pangenomes. Furthermore, our analysis also reveals that the removal of the TCSs significantly affects the fitness of the cell. Hence, they may be used as promising drug targets against bacteria.

scholarly journals Multiple Mechanisms of Action for Inhibitors of Histidine Protein Kinases from Bacterial Two-Component Systems

1999 ◽  
Vol 43 (7) ◽  
pp. 1693-1699 ◽  
Author(s):  
Jamese J. Hilliard ◽  
Raul M. Goldschmidt ◽  
Lisa Licata ◽  
Ellen Z. Baum ◽  
Karen Bush
Keyword(s):  
Pathogenic Bacteria ◽  
Response Regulator ◽  
Membrane Integrity ◽  
Bacterial Killing ◽  
Gram Positive Bacteria ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Bacterial Cell Membrane ◽  
Cellular Incorporation

ABSTRACT Many pathogenic bacteria utilize two-component systems consisting of a histidine protein kinase (HPK) and a response regulator (RR) for signal transduction. During the search for novel inhibitors, several chemical series, including benzoxazines, benzimidazoles, bis-phenols, cyclohexenes, trityls, and salicylanilides, were identified that inhibited the purified HPK-RR pairs KinA-Spo0F and NRII-NRI, with 50% inhibitory concentrations (IC50s) ranging from 1.9 to >500 μM and MICs ranging from 0.5 to >16 μg/ml for gram-positive bacteria. However, additional observations suggested that mechanisms other than HPK inhibition might contribute to antibacterial activity. In the present work, representative compounds from the six different series of inhibitors were analyzed for their effects on membrane integrity and macromolecular synthesis. At 4× MIC, 17 of 24 compounds compromised the integrity of the bacterial cell membrane within 10 min, as measured by uptake of propidium iodide. In this set, compounds with lower IC50s tended to cause greater membrane disruption. Eleven of 12 compounds inhibited cellular incorporation of radiolabeled thymidine and uridine >97% in 5 min and amino acids >80% in 15 min. The HPK inhibitor that allowed >25% precursor incorporation had no measurable MIC (>16 μg/ml). Fifteen of 24 compounds also caused hemolysis of equine erythrocytes. Thus, the antibacterial HPK inhibitors caused a rapid decrease in cellular incorporation of RNA, DNA, and protein precursors, possibly as a result of the concomitant disruption of the cytoplasmic membrane. Bacterial killing by these HPK inhibitors may therefore be due to multiple mechanisms, independent of HPK inhibition.

scholarly journals Pangenome analytics reveal two-component systems as conserved targets in ESKAPEE pathogens

2020 ◽  
Author(s):  
Akanksha Rajput ◽  
Yara Seif ◽  
Kumari Sonal Choudhary ◽  
Christopher Dalldorf ◽  
Saugat Poudel ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Sequence Variation ◽  
Response Regulator ◽  
Cellular Functions ◽  
Gene Orientation ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Sense And Respond ◽  
High Degree

AbstractBacteria sense and respond to environmental stimuli through two-component systems (TCSs), that are composed of histidine kinase sensing and response regulator elements. TCSs are ubiquitous and participate in numerous cellular functions. TCSs across the ESKAPEE pathogens, representing the leading causes of nosocomial infections, were characterized using pangenome analytics, including annotation, mapping, pangenomic status, gene orientation, sequence variation, and structure. Our findings fall into two categories. 1) phylogenetic distribution of TCSs: (i) the number and types of TCSs varies between species of the ESKAPEE pathogens; (ii) TCSs are group-specific, i.e., Gram-positive and Gram-negative, except for KdpDE; (iii) most TCSs are conserved among genomes of an ESKAPEE, except in Pseudomonas aeruginosa. 2) sequence variation: (i) at the operon level, the genomic architecture of a TCS operon stratifies into a few discrete classes; and (ii) at the gene sequence level, histidine kinases, responsible for signal sensing, show sequence and structural variability as compared to response regulators that show a high degree of conservation. Taken together, this first comprehensive pangenomic assessment of TCSs reveals a range of strategies deployed by the ESKAPEE pathogens to manifest pathogenicity and antibiotic resistance. It further suggests that the conserved features of TCSs makes them an attractive group of potential targets with which to address antibiotic resistance.

scholarly journals Multiple Two-Component Systems Modulate Alkali Generation in Streptococcus gordonii in Response to Environmental Stresses

2009 ◽  
Vol 191 (23) ◽  
pp. 7353-7362 ◽  
Author(s):  
Yaling Liu ◽  
Robert A. Burne
Keyword(s):  
Acid Tolerance ◽  
Low Ph ◽  
Arginine Deiminase ◽  
Streptococcus Gordonii ◽  
Anaerobic Conditions ◽  
Environmental Signals ◽  
Ph Values ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

ABSTRACT The oral commensal Streptococcus gordonii must adapt to constantly fluctuating and often hostile environmental conditions to persist in the oral cavity. The arginine deiminase system (ADS) of S. gordonii enables cells to produce, ornithine, ammonia, CO2, and ATP from arginine hydrolysis, augmenting the acid tolerance of the organism. The ADS genes are substrate inducible and sensitive to catabolite repression, mediated through ArcR and CcpA, respectively, but the system also requires low pH and anaerobic conditions for optimal activation. Here, we demonstrate that the CiaRH and ComDE two-component systems (TCS) are required for low-pH-dependent expression of ADS genes in S. gordonii. Further, the VicRK TCS is required for optimal ADS gene expression under anaerobic conditions and enhances the sensitivity of the operon to repression by oxygen. The known anaerobic activator of the ADS, Fnr-like protein (Flp), appeared to act independently of the Vic TCS. Mutants of S. gordonii lacking components of the CiaRH, ComDE, or VicRK grew more slowly in acidified media and were more sensitive to killing at lethal pH values and to agents that induce oxidative stress. This study provides the first evidence that TCS can regulate the ADS of bacteria in response to specific environmental signals and reveals some notable differences in the contribution of CiaRH, ComDE, and VicRK to viability and stress tolerance between the oral commensal S. gordonii and the oral pathogen Streptococcus mutans.

scholarly journals Unlimited multistability and Boolean logic in microbial signalling

2015 ◽  
Vol 12 (108) ◽  
pp. 20150234 ◽  
Author(s):  
Varun B. Kothamachu ◽  
Elisenda Feliu ◽  
Luca Cardelli ◽  
Orkun S. Soyer
Keyword(s):  
Response Regulator ◽  
Reaction Rates ◽  
Boolean Logic ◽  
Mathematical Framework ◽  
Core Network ◽  
Environmental Signals ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Logic Functions

The ability to map environmental signals onto distinct internal physiological states or programmes is critical for single-celled microbes. A crucial systems dynamics feature underpinning such ability is multistability. While unlimited multistability is known to arise from multi-site phosphorylation seen in the signalling networks of eukaryotic cells, a similarly universal mechanism has not been identified in microbial signalling systems. These systems are generally known as two-component systems comprising histidine kinase (HK) receptors and response regulator proteins engaging in phosphotransfer reactions. We develop a mathematical framework for analysing microbial systems with multi-domain HK receptors known as hybrid and unorthodox HKs. We show that these systems embed a simple core network that exhibits multistability, thereby unveiling a novel biochemical mechanism for multistability. We further prove that sharing of downstream components allows a system with n multi-domain hybrid HKs to attain 3 n steady states. We find that such systems, when sensing distinct signals, can readily implement Boolean logic functions on these signals. Using two experimentally studied examples of two-component systems implementing hybrid HKs, we show that bistability and implementation of logic functions are possible under biologically feasible reaction rates. Furthermore, we show that all sequenced microbial genomes contain significant numbers of hybrid and unorthodox HKs, and some genomes have a larger fraction of these proteins compared with regular HKs. Microbial cells are thus theoretically unbounded in mapping distinct environmental signals onto distinct physiological states and perform complex computations on them. These findings facilitate the understanding of natural two-component systems and allow their engineering through synthetic biology.

scholarly journals Two-Component FAD-Dependent Monooxygenases: Current Knowledge and Biotechnological Opportunities

Biology ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 42 ◽  
Author(s):  
Thomas Heine ◽  
Willem van Berkel ◽  
George Gassner ◽  
Karl-Heinz van Pée ◽  
Dirk Tischler
Keyword(s):  
Amino Acid ◽  
Aromatic Compounds ◽  
Amino Acid Metabolism ◽  
Flavin Adenine Dinucleotide ◽  
Acid Metabolism ◽  
Current Knowledge ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Valuable Compounds

Flavoprotein monooxygenases create valuable compounds that are of high interest for the chemical, pharmaceutical, and agrochemical industries, among others. Monooxygenases that use flavin as cofactor are either single- or two-component systems. Here we summarize the current knowledge about two-component flavin adenine dinucleotide (FAD)-dependent monooxygenases and describe their biotechnological relevance. Two-component FAD-dependent monooxygenases catalyze hydroxylation, epoxidation, and halogenation reactions and are physiologically involved in amino acid metabolism, mineralization of aromatic compounds, and biosynthesis of secondary metabolites. The monooxygenase component of these enzymes is strictly dependent on reduced FAD, which is supplied by the reductase component. More and more representatives of two-component FAD-dependent monooxygenases have been discovered and characterized in recent years, which has resulted in the identification of novel physiological roles, functional properties, and a variety of biocatalytic opportunities.

scholarly journals Identification of Multiple Substrates of the StkP Ser/Thr Protein Kinase in Streptococcus pneumoniae

2010 ◽  
Vol 192 (14) ◽  
pp. 3629-3638 ◽  
Author(s):  
Linda Nováková ◽  
Silvia Bezoušková ◽  
Petr Pompach ◽  
Petra Špidlová ◽  
Lenka Sasková ◽  
...  
Keyword(s):  
Cell Division ◽  
Streptococcus Pneumoniae ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Regulation Of Gene Expression ◽  
Dependent Manner ◽  
Α Subunit ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

ABSTRACT Monitoring the external environment and responding to its changes are essential for the survival of all living organisms. The transmission of extracellular signals in prokaryotes is mediated mainly by two-component systems. In addition, genomic analyses have revealed that many bacteria contain eukaryotic-type Ser/Thr protein kinases. The human pathogen Streptococcus pneumoniae encodes 13 two-component systems and has a single copy of a eukaryotic-like Ser/Thr protein kinase gene designated stkP. Previous studies demonstrated the pleiotropic role of the transmembrane protein kinase StkP in pneumococcal physiology. StkP regulates virulence, competence, and stress resistance and plays a role in the regulation of gene expression. To determine the intracellular signaling pathways controlled by StkP, we used a proteomic approach for identification of its substrates. We detected six proteins phosphorylated on threonine by StkP continuously during growth. We identified three new substrates of StkP: the Mn-dependent inorganic pyrophosphatase PpaC, the hypothetical protein spr0334, and the cell division protein DivIVA. Contrary to the results of a previous study, we did not confirm that the α-subunit of RNA polymerase is a target of StkP. We showed that StkP activation and substrate recognition depend on the presence of a peptidoglycan-binding domain comprising four extracellular penicillin-binding protein- and Ser/Thr kinase-associated domain (PASTA domain) repeats. We found that StkP is regulated in a growth-dependent manner and likely senses intracellular peptidoglycan subunits present in the cell division septa. In addition, stkP inactivation results in cell division defects. Thus, the data presented here suggest that StkP plays an important role in the regulation of cell division in pneumococcus.

scholarly journals Global Chromosome Topology and the Two-Component Systems in Concerted Manner Regulate Transcription in Streptomyces

mSystems ◽  
2021 ◽  
Author(s):  
Martyna Gongerowska-Jac ◽  
Marcin J. Szafran ◽  
Jakub Mikołajczyk ◽  
Justyna Szymczak ◽  
Magdalena Bartyńska ◽  
...  
Keyword(s):  
Soil Bacteria ◽  
Biologically Active ◽  
Complex Life Cycle ◽  
Regulation Mechanism ◽  
Environmental Signals ◽  
Component Systems ◽  
Chromosome Topology ◽  
Two Component ◽  
Two Component Systems ◽  
Transcriptional Regulation Mechanism

Streptomyces microbes, soil bacteria with complex life cycle, are the producers of a broad range of biologically active compounds (e.g., antibiotics). Streptomyces bacteria respond to various environmental signals using a complex transcriptional regulation mechanism. Understanding regulation of their gene expression is crucial for Streptomyces application as industrial organisms.

scholarly journals Regulating polymyxin resistance in Gram-negative bacteria: roles of two-component systems PhoPQ and PmrAB

2020 ◽  
Vol 15 (6) ◽  
pp. 445-459 ◽  
Author(s):  
Jiayuan Huang ◽  
Chen Li ◽  
Jiangning Song ◽  
Tony Velkov ◽  
Lushan Wang ◽  
...  
Keyword(s):  
Lipid A ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Regulatory Mechanisms ◽  
Two Component System ◽  
Gram Negative ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
New Strategies

Polymyxins (polymyxin B and colistin) are last-line antibiotics against multidrug-resistant Gram-negative pathogens. Polymyxin resistance is increasing worldwide, with resistance most commonly regulated by two-component systems such as PmrAB and PhoPQ. This review discusses the regulatory mechanisms of PhoPQ and PmrAB in mediating polymyxin resistance, from receiving an external stimulus through to activation of genes responsible for lipid A modifications. By analyzing the reported nonsynonymous substitutions in each two-component system, we identified the domains that are critical for polymyxin resistance. Notably, for PmrB 71% of resistance-conferring nonsynonymous mutations occurred in the HAMP (present in histidine kinases, adenylate cyclases, methyl accepting proteins and phosphatase) linker and DHp (dimerization and histidine phosphotransfer) domains. These results enhance our understanding of the regulatory mechanisms underpinning polymyxin resistance and may assist with the development of new strategies to minimize resistance emergence.

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