Open Access

Two‑component signaling pathways modulate drug resistance of Staphylococcus aureus (Review)

  • Authors:
    • Shizhou Wu
    • Kaifeng Lin
    • Yunjie Liu
    • Hui Zhang
    • Lei Lei
  • View Affiliations

  • Published online on: June 9, 2020     https://doi.org/10.3892/br.2020.1312
  • ArticleNumber: 5
  • Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

As the issues surrounding antibiotic‑resistant strains of Staphylococcus aureus (S. aureus) are becoming increasingly serious concerns, it is imperative to investigate new therapeutic targets to successfully treat patients with S. aureus infections. The two‑component signal transduction system is one of the primary pathways by which bacteria adapt to the external environment, and it serves an important role in regulating virulence gene expression, cell wall synthesis, biofilm formation and bacterial activity. There are 17 two‑component signaling pathways in S. aureus, among which WalKR/VicSR/YycGF, AirSR/YhcSR, vancomycin resistance associated regulator/sensor and LytRS have been demonstrated to serve vital roles in regulating bacterial resistance, and are hypothesized to be potential targets for the treatment of S. aureus infections. The present review assesses the mechanism of the two‑component signaling pathways associated with the development of S. aureus resistance.

1. Introduction

Staphylococcus aureus (S. aureus) is a Gram-positive coccus with low-GC content (1). Due to variations in certain genes in the bacterial genome and the introduction of exogenous genes, this strain exhibits different degrees of drug resistance against β-lactams, quinolones and aminoglycosides (1). Since osteomyelitis is caused by methicillin-resistant S. aureus (MRSA), investigating novel targets and methods for treating MRSA has become an urgent clinical need (2).

Bacteria need to regulate their metabolism in response to changes due to environmental stress, such as antibiotics, temperature and oligotrophy (3). Two-component signal transduction systems (TCSTs) are primary signaling mechanisms utilized by bacteria to regulate metabolism in response to environmental changes (3). The mechanisms underlying TCSTs regulatory systems are activated following physical or chemical stimuli from the external environment; the histidine protein kinase receptor proteins anchored to the cell membrane sense the change in the external environment and undergo phosphorylation. The phosphate group is transferred to the response regulator which undergoes phosphorylation, and this is mediated by phosphotransferase. Subsequently, the phosphorylated response regulators bind to the promoter sequences of the downstream target gene, thereby regulating its expression, upregulating expression of proteins which allow the bacteria to adapt to external environmental changes and enhance the adaptive viability of bacteria (4,5).

The two-component signaling pathways are widely found in prokaryotic bacteria, such as S. aureus (6). The entire genome of S. aureus has been analyzed and it has been demonstrated that there are 17 two-component signaling pathways involved in the regulation of bacterial physiological metabolism (7). S. aureus resistance is inextricably associated with the regulation of the two-component signaling pathway (8). The present review assesses the current body of literature available regarding the mechanisms of two-component signaling pathways, and the emergency of developing suitable therapeutics to combat drug resistant S. aureus infections.

2. WalKR/VicSR/YycGF two-component signaling pathway

WalKR is a highly conserved and specific two-component signaling pathway in Gram-positive bacteria with low GC-content (9). S. aureus is Gram-positive with low GC-content (10). The walKR gene is an essential gene that is involved in the regulation of cell wall synthesis and other types of physiological metabolism (10). Howden et al (11) analyzed 10 types of vancomycin-intermediate resistance in S. aureus (VISA) and three types of heterogeneous VISA (hVISA) strains via high-throughput sequencing. The results demonstrated that eight types of VISA and two types of hVISA strains harbored site mutations in the walKR gene, and that this gene exhibited the highest degree of mutational frequency (11), suggesting that the walKR gene serves an important role in the generation of VISA and hVISA strains. The walKR protein not only participates in the regulation of cell wall synthesis, but also specifically binds to the promoter regions of the lytM, atlA, ssaA and isaA genes to positively regulate the expression of autolysin and peptidoglycan hydrolase, so as to modify the surface structure of the cell wall, including shortening the length of sugar chains in the cell wall and decreasing the degree of cross-linking of peptidoglycan (11). By changing the phenotype of the cell wall to increase bacterial resistance, the effectiveness of antibiotics which target the cell wall, such as vancomycin, is suppressed (11,12).

Vancomycin is a glycopeptide antibiotic secreted by Streptomyces orientalis, which inhibits cell wall synthesis by binding to the D-alanyl-D-alanine residue on the cell wall (13). In the absence of cell wall protection, the soma is prone to rupture, thus acting as a bactericide. A previous study showed that the insertion of the strong promoter sequence IS256, in the promoter region of the walKR gene of the S. aureus VISA strain upregulates the expression of its downstream target protein and enhances metabolic processes involving the strain's cell wall, resulting in an increase in bacterial resistance (14). In addition, single nucleotide polymorphisms are another important factor which underlie changes in WalKR expression. Domains in the walKR gene of the VISA strain carry a site mutation of a single nucleotide. The A96T mutation in the walKR gene is the mutation of base G into base A at site 24673 of S. aureus. The mutated base is located in a conserved sequence of the walKR gene and is associated with a conformational change of protein regulation by phosphorylation (15). These site mutations result in a decrease in the activity of the WalKR protein, downregulating the expression of bacterial autolytic enzymes, inhibiting autolytic processed in bacteria and decreasing the sensitivity of the bacteria to the drug (11).

The protein expressed by the yycHI gene as a downstream target gene of WalKR, binds to the WalKR histidine kinase receptor to form a complex to inhibit the activation of WalKR, and thus negatively regulates the WalKR pathway (16). The mutation rate of the yycHI gene in the VISA strain isolated from a clinical trial was significantly higher compared with that of the vancomycin-sensitive strain (16). This may due to the fact that the mutation of yycHI gene resulted in weakening of the negative regulatory mechanism on the WalKRK pathway, enhanced cell wall modification and cell wall synthesis and improved bacterial resistance (11).

3. AirSR/YhcSR two-component signaling pathway

The AirSR two-component signaling pathway is closely associated with S. aureus resistance towards vancomycin. In S. aureus (NCTC8325, a prototypical strain of S. aureus stored at National Collection of Type Cultures) with an airSR gene mutation, the expression levels of ~30 genes associated with cell wall synthesis, such as cap, ddl and pbp1, is significantly decreased and the minimum inhibitory concentration of the airSR gene mutant against vancomycin is significantly decreased. Further investigation using EMSA technology showed that the AirR protein directly binds to the promoter sequences of cell wall-forming genes such as cap, ddl and pbp1. By positively regulating the expression of these genes, the anabolic process of the cell wall was promoted, which in turn increased the sensitivity of the bacteria to vancomycin (17).

The YhcSR gene is an essential gene in S. aureus that is primarily involved in the regulation of important physiological processes, such as nitrate respiratory metabolism (18). The nitrate respiratory metabolic pathway is a key metabolic pathway required for the survival of S. aureus in a hypoxic environment (19). In addition, the YhcR protein directly binds to the promoter regions of the opuC and lac genes, and positively regulates the expression of these two genes. The opuC gene primarily participates in the synthesis of ABC transporters, whereas the lac gene is primarily involved in the metabolic regulation of lactose and galactose (20).

4. Vancomycin resistance associated regulator/sensor (VraRS) two-component signaling pathway

VraRS two-component signaling pathway is another important pathway associated with vancomycin resistance. The thickness of the S. aureus cell wall is positively correlated with the degree of vancomycin resistance (21). Proteins such as PBP2, SgtB and MurZ are key proteins involved in the synthesis of the cell wall of S. aureus and are positively regulated by the VraRS two-component signaling pathway (22,23). Kuroda et al (24) found that the decrease in vancomycin sensitivity was associated with the increased expression of the vraRS gene in the resistant S. aureus strain, and the authors showed that the expression levels of the vraRS gene was significantly increased by placing S. aureus in a medium containing vancomycin. Further investigations of several other antibiotics that act on S. aureus and inhibit cell wall synthesis, such as teicoplanin, ceftizoxime, imipenem, bacitracin and cycloserine, were performed, and it was shown that the expression levels of the vraS gene were increased (24). Based on these results, it was hypothesized that when S. aureus is stimulated by cell wall synthesis inhibitors, the cell wall synthesis process is positively regulated through upregulating expression of the vraRS gene, thereby reducing the sensitivity to the antibiotics that inhibit cell wall synthesis.

5. LytRS two-component signaling pathway

Cationic antimicrobial peptides (CAPs) are a class of active peptides produced by host cells, which are involved in the body's innate immune system (25). CAPs bind to the bacterial cell membrane through electrostatic attraction. Due to the oil-water amphipathy, the small molecule active peptide is inserted into the cell membrane of bacteria, and destroy the integrity and increase the permeability of the cell membrane, leading to the lysis and death of cells (25). When the surface potential of the bacterial cell membrane is decreased by CAPs, the LytS receptor in the LytRS two-component signal undergoes autophosphorylation and activates the corresponding response regulatory protein, LytR. The LytR protein binds to the corresponding promoter regions of the downstream target genes, such as the irgAB gene (26). The irgAB gene is a downstream gene adjacent to the lytRS gene and is crucially involved in the synthesis of anti-perforin, which inhibits programmed cell death and lysis (27). Thus, the LytRS two-component signal regulates the upregulation of the irgAB gene, inhibits programmed cell death and autolytic enzyme activity of bacteria, and therefore enhances the drug resistance of bacteria.

Furthermore, the lytRS gene serves a role in regulating bacterial extracellular DNA, which is an important component of biofilms (28). When the surface potential of the bacterial cell membrane is decreased, the activation of this pathway subsequently decreases the secretion of extracellular DNA and inhibits the formation of biofilms (26). As the formation of the bacterial membrane improves bacterial resistance (29), the lytRS gene may decrease bacterial resistance by negatively regulating the secretion of extracellular DNA. Thus, the LytRS two-component signaling pathway may exhibit dual-regulation in the resistance of S. aureus. The yhcSR and vraRS genes in S. aureus are homologous to the yhcYZ and yvqEC genes in Bacteroides subtilis (B. subtilis). The yhcYZ and yvqEC genes in B. subtilis interact and regulate cell wall synthesis (30). Thus, it is hypothesized that yhcSR and vraRS genes may also employ similar mechanisms, namely, regulating cell wall synthesis.

6. GraRS/ApsRS two-component signaling pathway

Bacteriocin is a peptide substance that is self-synthesized by bacteria to inhibit the proliferation of other types of bacteria. These peptides are released into the cytoplasm with the assistance of the ATP-binding cassette (ABC) transport system (31). In addition to releasing its own bacteriocin, the ATP transport system also pumps exogenous bacteriocins out of the cytoplasm as a defense mechanism (32). Multiple ATP gene loci adjacent to the bicomponent signal were identified following the analysis of the gene locus of S. aureus (32). However, S. aureus has not been confirmed to possess bacteriocin synthesis-associated genes, and therefore these structural sites are hypothesized to be primarily associated with immune defense (33). High expression of genes associated with the two-component signaling pathway in GraRS is associated with VISA production (34). The GraRS two-component signaling pathway upregulates the expression of VraFG ATP transporter-associated genes, enhances efflux transport mechanisms in bacteria, increases transport of intracellular antibiotics, such as vancomycin and mitomycin B, out of the cytoplasm and prevents antibiotics from exerting antibacterial effects (35).

Conversely, the dlt and mprF genes decrease the negative charge on the surface of the cell membrane through modifying components, such as teichoic acid and phosphatidylglycerol on the surface of the cell membrane (36,37). The GraRS gene regulates the expression of dlt and mprF genes, and alters the negative potential on the cell wall surface, thereby decreasing the binding capacity of positively charged antibiotics (such as vancomycin and mitomycin B), and weakens their antibacterial effect (35). However, currently, the mechanism underlying the activation of the GraRS receptor protein is unknown, and the mechanism underlying the effect of the GraRS pathway on drug resistance requires further investigation.

7. BceRS/BraRS/NsaRS two-component signaling pathway

Similar to the GraRS/ApsRS two-component signaling pathway, the BceRS two-component signaling pathway gene is adjacent to the bceAB and vraDE genes of the ABC transport system (38). bceAB is located upstream of the bceRS gene, whereas vraDE is located ~80 bases downstream of the bceRS gene (38). The BceS protein activates the BceR protein following stimulation by external bacteriocin, and this results in the upregulation of the expression of bceAB and vraDE genes, thereby increasing transport of exogenous bacteriocins out of the cytoplasm by BceAB and VraDE proteins, preventing bacteriocin from acting as an antibacterial agent, and thus resulting in an increase in bacterial resistance (39). The minimum inhibitory concentration of S. aureus towards bacteriocin is decreased by 2-4-fold by reducing bceAB and vraDE gene expression (which encode the APC transporter gene) in S. aureus (38).

Nisin A. and Nukacin ISK-1 are type I bacteriocins secreted by Staphylococcus warner and Lactococcus lactis, respectively (40,41). Nisin A. exerts its bacteriostatic effects by acting on the cell membrane of bacteria to form pore complexes, which cause leakage and dissolution of cell fluid. Additionally, Nisin A also serves a role in inhibiting cell wall synthesis (40). Nukacin ISK-1 serves an antimicrobial role primarily via inhibiting the synthesis of the cell wall (41). When the two bacteriocins were co-cultured with the BraRS gene mutant S. aureus, the growth of the mutant strain was significantly inhibited (50-33%) (42). Thus, the BraRS gene exhibits significant regulatory effects on the symbiosis of S. aureus and the type I bacteriocin strain.

8. Hexose phosphate transporter regulator/sensor (HptRS) two-component signaling pathway

The HptRS two-component signaling pathway is primarily composed of hptA, hptRS and uhpT. HptA initiates autophosphorylation of the HptS protein by sensing changes in the concentration of surrounding phosphates, such as 3-phosphoric acid glucose, glucose-6-phosphate and Fosfomycin. uhpT is a downstream regulatory gene of the HptRS two-component signaling pathway. UhpT protein transports the aforementioned phosphates into the cytoplasm of bacteria to provide a source of carbon for physiological metabolism in bacteria (43). In addition to extracellular growth, S. aureus may invade host epithelial cells and acquire phosphate hexose from the cytoplasm of the host cell to maintain physiological metabolism in the bacteria (44) via the phosphoenolpyruvate phosphotransferase pathway (45). The molecular structure of Fosfomycin, a broad-spectrum antibiotic in clinical trials, is similar to phosphoenolpyruvate. Instead of being metabolized by the body, the antibiotic is excreted in its original form, thus it is widely used for the treatment of osteomyelitis due to its lower toxicity and fewer side effects (46). This type of antibiotic may be transported into the cytoplasm via the bacterial phosphohexose transporter to exert its antibiotic effects through competitively binding to UDP-N-acetylglucosamine-3-O-enolpyruvate transferase (encoded by the murA gene), inhibiting the synthesis of the peptidoglycan precursor, as well as interfering with the synthesis of the cell wall (47). However, when mutations occur in the HptPS two-component signaling pathway, the expression of UhpT protein is decreased, accompanied by a decrease in the uptake of Fosfomycin, and thus a decrease in the effectiveness of the drug, resulting in enhanced bacterial resistance (43).

9. Conclusion

As the incidence of MRSA infections is increasing each year, the therapeutic effects of antibiotics are becoming notably decreased. Although the emergence of novel treatment methods face enormous challenges, research based on new treatment concepts is required to combat emergent resistant MRSA strains. The two-component signaling pathway of S. aureus (Fig. 1) regulates the sensitivity of strains to antimicrobial agents through efflux mechanisms, regulation of cell wall anabolic processes, and inhibition of drug uptake. Furthermore, the two-component signaling pathways may regulate bacterial physiological metabolism and virulence factors, and improve the adaptability of bacteria to the external environment. Hence, an in-depth study of the mechanisms involved in the two-component signaling pathway of S. aureus may highlight novel potential targets for the treatment of osteomyelitis.

Acknowledgements

Not applicable.

Funding

This study was supported by the Sichuan Provincial Natural Science Foundation of China (grant no. 2018SZ0125), Sichuan Provincial Natural Science Foundation of China (grant no. 2019YFS0270) and the National Undergraduate Training Programs for Innovation and Entrepreneurship (grant no. C2019105797).

Availability of data and materials

Not applicable.

Authors' contributions

SW, KL, YL, HZ and LL conceived and designed the present review. SW, KL, YL, HZ and LL drafted and critically revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Ono D, Yamaguchi T, Hamada M, Sonoda S, Sato A, Aoki K, Kajiwara C, Kimura S, Fujisaki M, Tojo H, et al: Analysis of synergy between beta-lactams and anti-methicillin-resistant Staphylococcus aureus agents from the standpoint of strain characteristics and binding action. J Infect Chemother. 25:273–280. 2019.PubMed/NCBI View Article : Google Scholar

2 

Chuang YY and Huang YC: Molecular epidemiology of community-associated meticillin-resistant Staphylococcus aureus in Asia. Lancet Infect Dis. 13:698–708. 2013.PubMed/NCBI View Article : Google Scholar

3 

Mattos-Graner RO and Duncan MJ: Two-component signal transduction systems in oral bacteria. J Oral Microbiol. 9(1400858)2017.PubMed/NCBI View Article : Google Scholar

4 

Goulian M: Two-component signaling circuit structure and properties. Curr Opin Microbiol. 13:184–189. 2010.PubMed/NCBI View Article : Google Scholar

5 

Tierney AR and Rather PN: Roles of two-component regulatory systems in antibiotic resistance. Future Microbiol. 14:533–552. 2019.PubMed/NCBI View Article : Google Scholar

6 

Cheng RR, Morcos F, Levine H and Onuchic JN: Toward rationally redesigning bacterial two-component signaling systems using coevolutionary information. Proc Natl Acad Sci USA. 111:E563–E571. 2014.PubMed/NCBI View Article : Google Scholar

7 

Kuroda M, Ohta T, Uchiyama I, Baba T, Yuzawa H, Kobayashi I, Cui L, Oguchi A, Aoki K, Nagai Y, et al: Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet. 357:1225–1240. 2001.PubMed/NCBI View Article : Google Scholar

8 

Matsuo M, Kato F, Oogai Y, Kawai T, Sugai M and Komatsuzawa H: Distinct two-component systems in methicillin-resistant Staphylococcus aureus can change the susceptibility to antimicrobial agents. J Antimicrob Chemother. 65:1536–1537. 2010.PubMed/NCBI View Article : Google Scholar

9 

Xu T, Wu Y, Lin Z, Bertram R, Götz F, Zhang Y and Qu D: Identification of Genes controlled by the essential YycFG Two-component system reveals a role for biofilm modulation in Staphylococcus epidermidis. Front Microbiol. 8(724)2017.PubMed/NCBI View Article : Google Scholar

10 

Villanueva M, García B, Valle J, Rapún B, Ruiz de Los Mozos I, Solano C, Martí M, Penadés JR, Toledo-Arana A and Lasa I: Sensory deprivation in Staphylococcus aureus. Nat Commun. 9(523)2018.PubMed/NCBI View Article : Google Scholar

11 

Howden BP, McEvoy CR, Allen DL, Chua K, Gao W, Harrison PF, Bell J, Coombs G, Bennett-Wood V, Porter JL, et al: Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. PLoS Pathog. 7(e1002359)2011.PubMed/NCBI View Article : Google Scholar

12 

Kim T, Choi J, Lee S, Yeo KJ, Cheong HK and Kim KK: Structural studies on the extracellular domain of sensor Histidine Kinase YycG from Staphylococcus aureus and its functional implications. J Mol Biol. 428:3074–3089. 2016.PubMed/NCBI View Article : Google Scholar

13 

Peng H, Rao Y, Yuan W, Zheng Y, Shang W, Hu Z, Yang Y, Tan L, Xiong K, Li S, et al: Reconstruction of the vancomycin-susceptible Staphylococcus aureus phenotype from a vancomycin-intermediate S. aureus XN108. Front Microbiol. 9(2955)2018.PubMed/NCBI View Article : Google Scholar

14 

Jansen A, Türck M, Szekat C, Nagel M, Clever I and Bierbaum G: Role of insertion elements and yycFG in the development of decreased susceptibility to vancomycin in Staphylococcus aureus. Int J Med Microbiol. 297:205–215. 2007.PubMed/NCBI View Article : Google Scholar

15 

Bourret RB: Receiver domain structure and function in response regulator proteins. Curr Opin Microbiol. 13:142–149. 2010.PubMed/NCBI View Article : Google Scholar

16 

Cameron DR, Jiang JH, Kostoulias X, Foxwell DJ and Peleg AY: Vancomycin susceptibility in methicillin-resistant Staphylococcus aureus is mediated by YycHI activation of the WalRK essential two-component regulatory system. Sci Rep. 6(30823)2016.PubMed/NCBI View Article : Google Scholar

17 

Sun H, Yang Y, Xue T and Sun B: Modulation of cell wall synthesis and susceptibility to vancomycin by the two-component system AirSR in Staphylococcus aureus NCTC8325. BMC Microbiol. 13(286)2013.PubMed/NCBI View Article : Google Scholar

18 

Yan M, Hall JW, Yang J and Ji Y: The essential yhcSR two-component signal transduction system directly regulates the lac and opuCABCD operons of Staphylococcus aureus. PLoS One. 7(e50608)2012.PubMed/NCBI View Article : Google Scholar

19 

Yan M, Yu C, Yang J and Ji Y: The essential two-component system YhcSR is involved in regulation of the nitrate respiratory pathway of Staphylococcus aureus. J Bacteriol. 193:1799–1805. 2011.PubMed/NCBI View Article : Google Scholar

20 

Yan M, Hall JW, Yang J and Ji Y: The essential yhcSR Two-component signal transduction system directly regulates the lac and opuCABCD operons of Staphylococcus aureus. PLoS One. 7(e50608)2012.PubMed/NCBI View Article : Google Scholar

21 

Tajbakhsh G and Golemi-Kotra D: The dimerization interface in VraR is essential for induction of the cell wall stress response in Staphylococcus aureus: A potential druggable target. BMC Microbiol. 19(153)2019.PubMed/NCBI View Article : Google Scholar

22 

Hanaki H, Kuwahara-Arai K, Boyle-Vavra S, Daum RS, Labischinski H and Hiramatsu K: Activated cell-wall synthesis is associated with vancomycin resistance in methicillin-resistant Staphylococcus aureus clinical strains Mu3 and Mu50. J Antimicrob Chemother. 42:199–209. 1998.PubMed/NCBI View Article : Google Scholar

23 

Chen H, Xiong Z, Liu K, Li S, Wang R, Wang X, Zhang Y and Wang H: Transcriptional profiling of the two-component regulatory system VraSR in Staphylococcus aureus with low-level vancomycin resistance. Int J Antimicrob Agents. 47:362–367. 2016.PubMed/NCBI View Article : Google Scholar

24 

Kuroda M, Kuwaharaarai K and Hiramatsu K: Identification of the up- and down-regulated genes in vancomycin-resistant Staphylococcus aureus strains Mu3 and Mu50 by cDNA differential hybridization method. Biochem Biophys Res Commun. 269:485–490. 2000.PubMed/NCBI View Article : Google Scholar

25 

Omardien S, Brul S and Zaat SA: Antimicrobial activity of cationic antimicrobial peptides against gram-positives: Current progress made in understanding the mode of action and the response of bacteria. Front Cell Dev Biol. 4(111)2016.PubMed/NCBI View Article : Google Scholar

26 

Patel K and Golemi-Kotra D: Signaling mechanism by the Staphylococcus aureus two-component system LytSR: Role of acetyl phosphate in bypassing the cell membrane electrical potential sensor LytS. Version 2. F1000Res. 4(79)2015.PubMed/NCBI View Article : Google Scholar

27 

Sadykov MR and Bayles KW: The control of death and lysis in staphylococcal biofilms: A coordination of physiological signals. Curr Opin Microbiol. 15:211–215. 2012.PubMed/NCBI View Article : Google Scholar

28 

Mann EE, Rice KC, Boles BR, Endres JL, Ranjit D, Chandramohan L, Tsang LH, Smeltzer MS, Horswill AR and Bayles KW: Modulation of eDNA release and degradation affects Staphylococcus aureus biofilm maturation. PLoS One. 4(e5822)2009.PubMed/NCBI View Article : Google Scholar

29 

McCarthy H, Rudkin JK, Black NS, Gallagher L, O'Neill E and O'Gara JP: Methicillin resistance and the biofilm phenotype in Staphylococcus aureus. Front Cell Infect Microbiol. 5(1)2015.PubMed/NCBI View Article : Google Scholar

30 

Kobayashi K, Ogura M, Yamaguchi H, Yoshida K, Ogasawara N, Tanaka T and Fujita Y: Comprehensive DNA microarray analysis of Bacillus subtilis two-component regulatory systems. J Bacteriol. 183:7365–7370. 2001.PubMed/NCBI View Article : Google Scholar

31 

Crowe-McAuliffe C, Graf M, Huter P, Takada H, Abdelshahid M, Nováček J, Murina V, Atkinson GC, Hauryliuk V and Wilson DN: Structural basis for antibiotic resistance mediated by the Bacillus subtilis ABCF ATPase VmlR. Proc Natl Acad Sci USA. 115:8978–8983. 2018.PubMed/NCBI View Article : Google Scholar

32 

Liao F, Mo Z, Gu W, Xu W, Fu X and Zhang Y: A comparative genomic analysis between methicillin-resistant Staphylococcus aureus strains of hospital acquired and community infections in Yunnan province of China. BMC Infect Dis. 20(137)2020.PubMed/NCBI View Article : Google Scholar

33 

Gardete S and Tomasz A: Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest. 124:2836–2840. 2014.PubMed/NCBI View Article : Google Scholar

34 

Zeng D, Debabov D, Hartsell TL, Cano RJ, Adams S, Schuyler JA, McMillan R and Pace JL: Approved Glycopeptide antibacterial drugs: Mechanism of action and resistance. Cold Spring Harb Perspect Med. 6(a026989)2016.PubMed/NCBI View Article : Google Scholar

35 

Chaili S, Cheung AL, Bayer AS, Xiong YQ, Waring AJ, Memmi G, Donegan N, Yang SJ and Yeaman MR: The GraS Sensor in Staphylococcus aureus mediates resistance to host defense peptides differing in mechanisms of action. Infect Immun. 84:459–466. 2015.PubMed/NCBI View Article : Google Scholar

36 

Mechler L, Bonetti EJ, Reichert S, Flötenmeyer M, Schrenzel J, Bertram R, François P and Götz F: Daptomycin tolerance in the Staphylococcus aureus pitA6 mutant is due to Upregulation of the dlt operon. Antimicrob Agents Chemother. 60:2684–2691. 2016.PubMed/NCBI View Article : Google Scholar

37 

Kanesaka I, Fujisaki S, Aiba Y, Watanabe S, Mikawa T, Katsuse AK, Takahashi H, Cui L and Kobayashi I: Characterization of compensatory mutations associated with restoration of daptomycin-susceptibility in daptomycin non-susceptible methicillin-resistant Staphylococcus aureus and the role mprF mutations. J Infect Chemother. 25:1–5. 2019.PubMed/NCBI View Article : Google Scholar

38 

Kawada-Matsuo M, Yoshida Y, Nakamura N and Komatsuzawa H: Role of two-component systems in the resistance of Staphylococcus aureus to antibacterial agents. Virulence. 2:427–430. 2011.PubMed/NCBI View Article : Google Scholar

39 

Yang Y, Luo M, Zhou H, Li C, Luk A, Zhao G, Fung K and Ip M: Role of Two-component system response regulator bceR in the antimicrobial resistance, virulence, biofilm formation, and stress response of group B streptococcus. Front Microbiol. 10(10)2019.PubMed/NCBI View Article : Google Scholar

40 

Hyde AJ, Parisot J, McNichol A and Bonev BB: Nisin-induced changes in Bacillus morphology suggest a paradigm of antibiotic action. Proc Natl Acad Sci USA. 103:19896–19901. 2006.PubMed/NCBI View Article : Google Scholar

41 

Islam MR, Nishie M, Nagao J, Zendo T, Keller S, Nakayama J, Kohda D, Sahl HG and Sonomoto K: Ring A of nukacin ISK-1: A lipid II-binding motif for type-A(II) lantibiotic. J Am Chem Soc. 134:3687–3690. 2012.PubMed/NCBI View Article : Google Scholar

42 

Kawada-Matsuo M, Yoshida Y, Zendo T, Nagao J, Oogai Y, Nakamura Y, Sonomoto K, Nakamura N and Komatsuzawa H: Three distinct two-component systems are involved in resistance to the class I bacteriocins, Nukacin ISK-1 and nisin A, in Staphylococcus aureus. PLoS One. 8(e69455)2013.PubMed/NCBI View Article : Google Scholar

43 

Park JY, Kim JW, Moon BY, Lee J, Fortin YJ, Austin FW, Yang SJ and Seo KS: Characterization of a novel two-component regulatory system, HptRS, the regulator for the hexose phosphate transport system in Staphylococcus aureus. Infect Immun. 83(1620)2015.PubMed/NCBI View Article : Google Scholar

44 

Postma PW, Lengeler JW and Jacobson GR: Phosphoenolpyruvate: Carbohydrate phosphotransferase systems of bacteria. Microbiol Rev. 57:232–269. 1993.PubMed/NCBI

45 

Fraunholz M and Sinha B: Intracellular Staphylococcus aureus: Live-in and let die. Front Cell Infect Microbiol. 2(43)2012.PubMed/NCBI View Article : Google Scholar

46 

Trinh TD, Smith JR and Rybak MJ: Parenteral Fosfomycin for the treatment of multidrug resistant bacterial infections: The rise of the epoxide. Pharmacotherapy. 39:1077–1094. 2019.PubMed/NCBI View Article : Google Scholar

47 

Hrast M, Rožman K, Jukič M, Patin D, Gobec S and Sova M: Synthesis and structure-activity relationship study of novel quinazolinone-based inhibitors of MurA. Bioorg Med Chem Lett. 27:3529–3533. 2017.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

August-2020
Volume 13 Issue 2

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wu S, Lin K, Liu Y, Zhang H and Lei L: Two‑component signaling pathways modulate drug resistance of Staphylococcus aureus (Review). Biomed Rep 13: 5, 2020
APA
Wu, S., Lin, K., Liu, Y., Zhang, H., & Lei, L. (2020). Two‑component signaling pathways modulate drug resistance of Staphylococcus aureus (Review). Biomedical Reports, 13, 5. https://doi.org/10.3892/br.2020.1312
MLA
Wu, S., Lin, K., Liu, Y., Zhang, H., Lei, L."Two‑component signaling pathways modulate drug resistance of Staphylococcus aureus (Review)". Biomedical Reports 13.2 (2020): 5.
Chicago
Wu, S., Lin, K., Liu, Y., Zhang, H., Lei, L."Two‑component signaling pathways modulate drug resistance of Staphylococcus aureus (Review)". Biomedical Reports 13, no. 2 (2020): 5. https://doi.org/10.3892/br.2020.1312