In silico identification of auxiliary factors genes required for β-lactam resistance
DOI:
https://doi.org/10.47187/cssn.Vol14.Iss1.213Palabras clave:
auxiliary factors, Staphylococcus aureus, β-lactam antibiotic, antibiotic resistance×,, in silico identification.Resumen
Staphylococcus aureus is a type of bacteria commonly found on the skin and in the nasal passages of healthy individuals. However, it can also cause a range of infections in clinical settings. One of the most concerning aspects of S. aureus is its ability to develop antibiotic resistance. Methicillin-resistant S. aureus (MRSA) is a strain of the bacteria that is resistant to many antibiotics and can be difficult to treat. The primary mechanism of methicillin resistance in MRSA is the presence of the mecA gene, which encodes for a modified penicillin-binding protein known as PBP2a. This protein has a lower affinity for β-lactam antibiotics. Another gene, blaZ, is also present in MRSA and encodes for a β-lactamase enzyme that can hydrolyse and inactivate β-lactam antibiotics such as penicillin. In addition, there are several auxiliary factors that can contribute to β-lactam resistance. They can include efflux pumps, enzymes that modify or degrade antibiotics, and bacterial cell wall modifications that reduce the affinity of antibiotics for their targets. In this study, with the aid of the in silico identification method, we identify the novel auxiliary factors aux1, aux2, aux4, aux11, aux14, aux16 and aux19. Next, we show that aux2, aux4, aux11, aux14 are not directly involved in β-lactam resistance, but may contribute through other mechanisms that decrease the efficacy of these antibiotics, whereas aux16 and aux19 are directly associated with β-lactam and bacitracin resistance, respectively. Understanding the various auxiliary factors that contribute to beta-lactam resistance can help guide the development of new antibiotics and other therapeutic strategies.
Descargas
Citas
Kwiecinski JM, Horswill AR. Staphylococcus aureus bloodstream infections: pathogenesis and regulatory mechanisms. Curr Opin Microbiol. 2020;53:51-60.
Oliveira K, Viegas C, Ribeiro E. MRSA Colonization in Workers from Different Occupational Environments—A One Health Approach Perspective. Atmosphere. 2022;13(5):658.
Dittmann K, Schmidt T, Müller G, Cuny C, Holtfreter S, Troitzsch D, et al. Susceptibility of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) to chlorhexidine digluconate, octenidine dihydrochloride, polyhexanide, PVP-iodine and triclosan in comparison to hospital-acquired MRSA (HA-MRSA) and community-aquired MRSA (CA-MRSA): a standardized comparison. Antimicrob Resist Infect Control. 2019;8:122.
Turner NA, Sharma-Kuinkel BK, Maskarinec SA, Eichenberger EM, Shah PP, Carugati M, et al. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nature Reviews Microbiology. 2019;17(4):203-18.
Okiki PA, Eromosele ES, Ade-Ojo P, Sobajo OA, Idris OO, Agbana RD. Occurrence of mecA and blaZ genes in methicillin-resistant Staphylococcus aureus associated with vaginitis among pregnant women in Ado-Ekiti, Nigeria. New Microbes New Infect. 2020;38:100772.
Mikkelsen K, Sirisarn W, Alharbi O, Alharbi M, Liu H, Nøhr-Meldgaard K, et al. The Novel Membrane-Associated Auxiliary Factors AuxA and AuxB Modulate β-lactam Resistance in MRSA by stabilizing Lipoteichoic Acids. International Journal of Antimicrobial Agents. 2021;57(3):106283.
Typas A, Banzhaf M, Gross CA, Vollmer W. From the regulation of peptidoglycan synthesis to bacterial growth and morphology. Nature Reviews Microbiology. 2012;10(2):123-36.
Oliveira IA, Allonso D, Fernandes TVA, Lucena DMS, Ventura GT, Dias WB, et al. Enzymatic and structural properties of human glutamine:fructose-6-phosphate amidotransferase 2 (hGFAT2). J Biol Chem. 2021;296:100180.
Hummels KR, Berry SP, Li Z, Taguchi A, Min JK, Walker S, et al. Coordination of bacterial cell wall and outer membrane biosynthesis. Nature. 2023;615(7951):300-4.
Hrast M, Rožman K, Ogris I, Škedelj V, Patin D, Sova M, et al. Evaluation of the published kinase inhibitor set to identify multiple inhibitors of bacterial ATP-dependent mur ligases. J Enzyme Inhib Med Chem. 2019;34(1):1010-7.
Song Y, Lee JS, Shin J, Lee GM, Jin S, Kang S, et al. Functional cooperation of the glycine synthase-reductase and Wood–Ljungdahl pathways for autotrophic growth of Clostridium drakei. Proceedings of the National Academy of Sciences. 2020;117(13):7516-23.
Monteiro JM, Münch D, Filipe SR, Schneider T, Sahl H-G, Pinho MG. The pentaglycine bridges of Staphylococcus aureus peptidoglycan are essential for cell integrity. bioRxiv. 2018:479006.
Travis BA, Peck JV, Salinas R, Dopkins B, Lent N, Nguyen VD, et al. Molecular dissection of the glutamine synthetase-GlnR nitrogen regulatory circuitry in Gram-positive bacteria. Nature Communications. 2022;13(1):3793.
Nöldeke ER, Muckenfuss LM, Niemann V, Müller A, Störk E, Zocher G, et al. Structural basis of cell wall peptidoglycan amidation by the GatD/MurT complex of Staphylococcus aureus. Sci Rep. 2018;8(1):12953.
Kuk ACY, Hao A, Lee S-Y. Structure and Mechanism of the Lipid Flippase MurJ. Annual Review of Biochemistry. 2022;91(1):705-29.
Liu X, Meiresonne NY, Bouhss A, den Blaauwen T. FtsW activity and lipid II synthesis are required for recruitment of MurJ to midcell during cell division in Escherichia coli. Molecular Microbiology. 2018;109(6):855-84.
Wacnik K, Rao VA, Chen X, Lafage L, Pazos M, Booth S, et al. Penicillin-Binding Protein 1 (PBP1) of Staphylococcus aureus Has Multiple Essential Functions in Cell Division. mBio. 2022;13(4):e0066922.
da Costa TM, de Oliveira CR, Chambers HF, Chatterjee SS. PBP4: A New Perspective on Staphylococcus aureus β-Lactam Resistance. Microorganisms. 2018;6(3).
Roch M, Lelong E, Panasenko OO, Sierra R, Renzoni A, Kelley WL. Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 for Staphylococcus aureus MRSA β-lactam resistance. Commun Biol. 2019;2:417.
Dalal V, Kumar P, Rakhaminov G, Qamar A, Fan X, Hunter H, et al. Repurposing an Ancient Protein Core Structure: Structural Studies on FmtA, a Novel Esterase of Staphylococcus aureus. Journal of Molecular Biology. 2019;431(17):3107-23.
G CB, Sahukhal GS, Elasri MO. Role of the msaABCR Operon in Cell Wall Biosynthesis, Autolysis, Integrity, and Antibiotic Resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 2019;63(10).
Walter A, Unsleber S, Rismondo J, Jorge AM, Peschel A, Gründling A, et al. Phosphoglycerol-type wall and lipoteichoic acids are enantiomeric polymers differentiated by the stereospecific glycerophosphodiesterase GlpQ. J Biol Chem. 2020;295(12):4024-34.
Chee Wezen X, Chandran A, Eapen RS, Waters E, Bricio-Moreno L, Tosi T, et al. Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors. Journal of Chemical Information and Modeling. 2022;62(10):2586-99.
Vickery CR, Wood BM, Morris HG, Losick R, Walker S. Reconstitution of Staphylococcus aureus Lipoteichoic Acid Synthase Activity Identifies Congo Red as a Selective Inhibitor. Journal of the American Chemical Society. 2018;140(3):876-9.
Zeng J, Platig J, Cheng TY, Ahmed S, Skaf Y, Potluri LP, et al. Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility. PLoS Pathog. 2020;16(4):e1008452.
Jenul C, Horswill AR. Regulation of Staphylococcus aureus Virulence. Microbiol Spectr. 2019;7(2).
Bleul L, Francois P, Wolz C. Two-Component Systems of S. aureus: Signaling and Sensing Mechanisms. Genes (Basel). 2021;13(1).
Miragaia M. Factors Contributing to the Evolution of mecA-Mediated β-lactam Resistance in Staphylococci: Update and New Insights From Whole Genome Sequencing (WGS). Frontiers in Microbiology. 2018;9.
Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, et al. β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019;431(18):3472-500.
Yadav AK, Espaillat A, Cava F. Bacterial Strategies to Preserve Cell Wall Integrity Against Environmental Threats. Front Microbiol. 2018;9:2064.
De Lencastre H, Wu SW, Pinho MG, Ludovice AM, Filipe S, Gardete S, et al. Antibiotic resistance as a stress response: complete sequencing of a large number of chromosomal loci in Staphylococcus aureus strain COL that impact on the expression of resistance to methicillin. Microb Drug Resist. 1999;5(3):163-75.
Xu J-Z, Ruan H-Z, Liu L-M, Wang L-P, Zhang W-G. Overexpression of thermostable meso-diaminopimelate dehydrogenase to redirect diaminopimelate pathway for increasing L-lysine production in Escherichia coli. Scientific Reports. 2019;9(1):2423.
Boyd SE, Livermore DM, Hooper DC, Hope WW. Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline. Antimicrobial Agents and Chemotherapy. 2020;64(10):e00397-20.
Aslanli A, Domnin M, Stepanov N, Efremenko E. "Universal" Antimicrobial Combination of Bacitracin and His(6)-OPH with Lactonase Activity, Acting against Various Bacterial and Yeast Cells. Int J Mol Sci. 2022;23(16).
Berger-Bächi B. Insertional inactivation of staphylococcal methicillin resistance by Tn551. J Bacteriol. 1983;154(1):479-87.
Händel N, Schuurmans JM, Brul S, ter Kuile BH. Compensation of the metabolic costs of antibiotic resistance by physiological adaptation in Escherichia coli. Antimicrob Agents Chemother. 2013;57(8):3752-62.
Hernández SB, Dörr T, Waldor MK, Cava F. Modulation of Peptidoglycan Synthesis by Recycled Cell Wall Tetrapeptides. Cell Rep. 2020;31(4):107578.
Gaucher F, Rabah H, Kponouglo K, Bonnassie S, Pottier S, Dolivet A, et al. Intracellular osmoprotectant concentrations determine Propionibacterium freudenreichii survival during drying. Applied Microbiology and Biotechnology. 2020;104(7):3145-56.
Yang N, Ding R, Liu J. Synthesizing glycine betaine via choline oxidation pathway as an osmoprotectant strategy in Haloferacales. Gene. 2022;847:146886.
McNeil SD, Nuccio ML, Hanson AD. Betaines and Related Osmoprotectants. Targets for Metabolic Engineering of Stress Resistance1. Plant Physiology. 1999;120(4):945-9.
Salzer A, Keinhörster D, Kästle C, Kästle B, Wolz C. Small Alarmone Synthetases RelP and RelQ of Staphylococcus aureus Are Involved in Biofilm Formation and Maintenance Under Cell Wall Stress Conditions. Front Microbiol. 2020;11:575882.
Magnusson LU, Farewell A, Nyström T. ppGpp: a global regulator in Escherichia coli. Trends Microbiol. 2005;13(5):236-42.
Kudrin P, Dzhygyr I, Ishiguro K, Beljantseva J, Maksimova E, Oliveira SRA, et al. The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA. Nucleic Acids Res. 2018;46(4):1973-83.
Fritsch VN, Loi VV, Busche T, Tung QN, Lill R, Horvatek P, et al. The alarmone (p)ppGpp confers tolerance to oxidative stress during the stationary phase by maintenance of redox and iron homeostasis in Staphylococcus aureus. Free Radic Biol Med. 2020;161:351-64.
Madsen CD, Hein J, Workman CT. Systematic inference of indirect transcriptional regulation by protein kinases and phosphatases. PLoS Comput Biol. 2022;18(6):e1009414.
