Analysis of random mutations in Salmonella Gallinarum dihydropteroate synthase conferring sulfonamide resistance.
Dihydropteroate synthase
Mutant analysis
Protein modeling
Salmonella enterica serovar Gallinarum
Sulfonamide
Journal
Archives of microbiology
ISSN: 1432-072X
Titre abrégé: Arch Microbiol
Pays: Germany
ID NLM: 0410427
Informations de publication
Date de publication:
31 Oct 2023
31 Oct 2023
Historique:
received:
29
08
2023
accepted:
29
09
2023
revised:
26
09
2023
medline:
2
11
2023
pubmed:
31
10
2023
entrez:
31
10
2023
Statut:
epublish
Résumé
In bacteria and primitive eukaryotes, sulfonamide antibiotics block the folate pathway by inhibiting dihydropteroate synthase (FolP) that combines para-aminobenzoic acid (pABA) and dihydropterin pyrophosphate (DHPP) to form dihydropteroic acid (DHP), a precursor for tetrahydrofolate synthesis. However, the emergence of resistant strains has severely compromised the use of pABA mimetics as sulfonamide drugs. Salmonella enterica serovar Gallinarum (S. Gallinarum) is a significant source of antibiotic-resistant infections in poultry. Here, a sulfonamide-resistant FolP mutant library of S. Gallinarum was generated through random mutagenesis. Among resistant strains, substitution of amino acid Arginine 171 with Proline (R171P) in the FolP protein conferred the highest resistance against sulfonamide. Substitution of Phe28 with Leu or Ile (F28L/I) led to modest sulfonamide resistance. Structural modeling indicates that R171P and Phenylalanine 28 with leucine or isoleucine (F28L/I) substitution mutations are located far from the substrate-binding site and cause insignificant conformational changes in the FolP protein. Rather, in silico studies suggest that the mutations altered the stability of the protein, potentially resulting in sulfonamide resistance. Identification of specific mutations in FolP that confer resistance to sulfonamide would contribute to our understanding of the molecular mechanisms of antibiotic resistance.
Identifiants
pubmed: 37906281
doi: 10.1007/s00203-023-03696-5
pii: 10.1007/s00203-023-03696-5
doi:
Substances chimiques
Dihydropteroate Synthase
EC 2.5.1.15
4-Aminobenzoic Acid
TL2TJE8QTX
Anti-Bacterial Agents
0
Sulfanilamide
21240MF57M
Sulfonamides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
363Subventions
Organisme : Starting growth Technological R&D Program (TIPS Program) funded by the Ministry of SMEs and Startups (MSS, Korea) in 2021
ID : No. S3130592
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Achari A, Somers DO, Champness JN, Bryant PK, Rosemond J, Stammers DK (1997) Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nat Struct Biol 4:490–497
doi: 10.1038/nsb0697-490
pubmed: 9187658
Aspinall TV, Joynson DH, Guy E, Hyde JE, Sims PF (2002) The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis. J Infect Dis 185(11):1637–1643. https://doi.org/10.1086/340577
doi: 10.1086/340577
pubmed: 12023770
Babaoglu K, Qi J, Lee RE, White SW (2004) Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis: mechanism and novel inhibitor design. Structure (london, England: 1993) 12(9):1705–1717
doi: 10.1016/j.str.2004.07.011
pubmed: 15341734
Baca AM, Sirawaraporn R, Turley S, Sirawaraporn W, Hol WGJ (2000) Crystal structure of mycobacterium tuberculosis 6-hydroxymethyl-7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action. J Mol Biol 302:1193–1212
doi: 10.1006/jmbi.2000.4094
pubmed: 11007651
Banner DW, Bloomer AC, Petsko GA, Phillips DC, Pogson CI, Wilson IA, Corran PH, Furth AJ, Milman JD, Offord RE, Priddle JD, Waley SG (1975) Structure of chicken muscle triose phosphate isomerase determined crystallographically at 2.5 angstrom resolution using amino acid sequence data. Nature 255(5510):609–614. https://doi.org/10.1038/255609a0
doi: 10.1038/255609a0
pubmed: 1134550
Bermingham A, Derrick JP (2002) The folic acid biosynthesis pathway in bacteria: evaluation of potential for or antibacterial drug discovery. BioEssays 24:637–648. https://doi.org/10.1002/bies.10114
doi: 10.1002/bies.10114
pubmed: 12111724
Centers for Disease Control and Prevention (CDC) (2013) Antibiotic resistance threats in the United States. Available online: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf . Accessed on 24 Oct 2017
Dallakyan S, Olson AJ (2015) Small-molecule library screening by docking with PyRx. Methods in molecular biology (Clifton, N.J.) 1263:243–250. https://doi.org/10.1007/978-1-4939-2269-7_19
Dallas WS, Gowen JE, Ray PH, Cox MJ, Dev IK (1992) Cloning, sequencing, and enhanced expression of the dihydropteroate synthase gene of Escherichia coli MC4100. J Bacteriol 174:5961–5970. https://doi.org/10.1128/jb.174.18.5961-5970.1992
doi: 10.1128/jb.174.18.5961-5970.1992
pubmed: 1522070
pmcid: 207134
Enne VI, King A, Livermore DM, Hall LM (2002) Sulfonamide resistance in Haemophilus influenzae mediated by acquisition of sul2 or a short insertion in chromosomal folP. Antimicrob Agents Chemother 46(6):1934–1939. https://doi.org/10.1128/AAC.46.6.1934-1939.2002
doi: 10.1128/AAC.46.6.1934-1939.2002
pubmed: 12019111
pmcid: 127234
Eriksson AE, Baase WA, Zhang XJ, Heinz DW, Blaber M, Baldwin EP, Matthews BW (1992) Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. Science (new York, n.y.) 255(5041):178–183. https://doi.org/10.1126/science.1553543
doi: 10.1126/science.1553543
pubmed: 1553543
Fermer C, Kristiansen BE, Sköld O, Swedberg G (1995) Sulfonamide resistance in Neisseria meningitidis as defined by site-directed mutagenesis could have its origin in other species. J Bacteriol 177:4669–4675. https://doi.org/10.1128/jb.177.16.4669-4675.1995
doi: 10.1128/jb.177.16.4669-4675.1995
pubmed: 7642493
pmcid: 177231
Fermér C, Swedberg G (1997) Adaptation to sulfonamide resistance in Neisseria meningitidis may have required compensatory changes to retain enzyme function: kinetic analysis of dihydropteroate synthases from N meningitidis expressed in a knockout mutant of Escherichia coli. J Bacteriol 179(3):831–837. https://doi.org/10.1128/jb.179.3.831-837.1997
doi: 10.1128/jb.179.3.831-837.1997
pubmed: 9006040
pmcid: 178767
Gibreel A, Sköld O (1999) Sulfonamide resistance in clinical isolates of Campylobacter jejuni: mutational changes in the chromosomal dihydropteroate synthase. Antimicrob Agents Chemother 43(9):2156–2160. https://doi.org/10.1128/AAC.43.9.2156
doi: 10.1128/AAC.43.9.2156
pubmed: 10471557
pmcid: 89439
Griffith EC, Wallace MJ, Wu Y, Kumar G, Gajewski S, Jackson P, Phelps GA, Zheng Z, Rock CO, Lee RE, White SW (2018) the structural and functional basis for recurring sulfa drug resistance mutations in Staphylococcus aureus dihydropteroate synthase. Front Microbiol 9:1369. https://doi.org/10.3389/fmicb.2018.01369
doi: 10.3389/fmicb.2018.01369
pubmed: 30065703
pmcid: 6057106
Haasum Y, Ström K, Wehelie R, Luna V, Roberts MC, Maskell JP, Hall LM, Swedberg G (2001) Amino acid repetitions in the dihydropteroate synthase of Streptococcus pneumoniae lead to sulfonamide resistance with limited effects on substrate K(m). Antimicrob Agents Chemother 45(3):805–809. https://doi.org/10.1128/AAC.45.3.805-809.2001
doi: 10.1128/AAC.45.3.805-809.2001
pubmed: 11181365
pmcid: 90378
Hampele IC, D’Arcy A, Dale GE, Kostrewa D, Nielsen J, Oefner C, Page MG, Schönfeld HJ, Stüber D, Then RL (1997) Structure and function of the dihydropteroate synthase from Staphylococcus aureus. J Mol Biol 268(1):21–30. https://doi.org/10.1006/jmbi.1997.0944
doi: 10.1006/jmbi.1997.0944
pubmed: 9149138
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596(7873):583–589
doi: 10.1038/s41586-021-03819-2
pubmed: 34265844
pmcid: 8371605
Kai M, Matsuoka M, Nakata N, Maeda S, Gidoh M, Maeda Y, Hashimoto K, Kobayashi K, Kashiwabara Y (1999) Diaminodiphenylsulfone resistance of Mycobacterium leprae due to mutations in the dihydropteroate synthase gene. FEMS Microbiol Lett 177(2):231–235. https://doi.org/10.1111/j.1574-6968.1999.tb13737.x
doi: 10.1111/j.1574-6968.1999.tb13737.x
pubmed: 10474189
Kazanjian P, Locke AB, Hossler PA, Lane BR, Bartlett MS, Smith JW, Cannon M, Meshnick SR (1998) Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients. AIDS (london, England) 12(8):873–878. https://doi.org/10.1097/00002030-199808000-00009
doi: 10.1097/00002030-199808000-00009
pubmed: 9631140
Koyanagi T, Yoshida E, Minami H, Katayama T, Kumagai H (2008) A rapid, simple, and effective method of constructing a randomly mutagenized plasmid library free from ligation. Biosci Biotechnol Biochem 72(4):1134–1137. https://doi.org/10.1271/bbb.70814
doi: 10.1271/bbb.70814
pubmed: 18391449
Lane BR, Ast JC, Hossler PA, Mindell DP, Bartlett MS, Smith JW, Meshnick SR (1997) Dihydropteroate synthase polymorphisms in Pneumocystis carinii. J Infect Dis 175(2):482–485. https://doi.org/10.1093/infdis/175.2.482
doi: 10.1093/infdis/175.2.482
pubmed: 9203679
Li Q, Cheng T, Wang Y, Bryant SH (2010) PubChem as a public resource for drug discovery. Drug Discov Today 15(23–24):1052–1057. https://doi.org/10.1016/j.drudis.2010.10.003
doi: 10.1016/j.drudis.2010.10.003
pubmed: 20970519
pmcid: 3010383
Lilkova E et al (2015) The PyMOL Molecular Graphics System, Version 2.0 Schrodinger. LLC
Lister SA, Barrow P (2008) Enterobacteriaceae. Poult Dis. https://doi.org/10.1016/B978-0-7020-2862-5.50013-1
doi: 10.1016/B978-0-7020-2862-5.50013-1
Ma L, Kovacs JA (2001) Genetic analysis of multiple loci suggests that mutations in the Pneumocystis carinii f. sp. hominis dihydropteroate synthase gene arose independently in multiple strains. Antimicrob Agents Chemother 45(11):3213–3215. https://doi.org/10.1128/AAC.45.11.3213-3215.2001
doi: 10.1128/AAC.45.11.3213-3215.2001
pubmed: 11600382
pmcid: 90808
Robert X, Gouet P (2014) Deciphering key features in protein structures with the new ENDscript server. Nucl Acids Res 42(W1):W320–W324. https://doi.org/10.1093/nar/gku316
doi: 10.1093/nar/gku316
pubmed: 24753421
pmcid: 4086106
Rodrigues CH, Pires DE, Ascher DB (2018) DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res 46(W1):W350–W355. https://doi.org/10.1093/nar/gky300
doi: 10.1093/nar/gky300
pubmed: 29718330
pmcid: 6031064
Roland S, Ferone R, Harvey RJ, Styles VL, Morrison RW (1979) The characteristics and significance of sulfonamides as substrates for Escherichia coli dihydropteroate synthase. J Biol Chem 254:10337–10345
doi: 10.1016/S0021-9258(19)86714-5
pubmed: 385600
Scallan E, Hoekstra RM, Angulo FJ, Tauxe RV, Widdowson MA, Roy SL, Jones JL, Griffin PM (2011) Foodborne illness acquired in the United States–major pathogens. Emerg Infect Dis 17(1):7–15. https://doi.org/10.3201/eid1701.p11101
doi: 10.3201/eid1701.p11101
pubmed: 21192848
pmcid: 3375761
Sköld O (2000) Sulfonamide resistance: mechanisms and trends. Drug Resistance Updat Rev Commentar Antimicrob Anticancer Chemother 3(3):155–160. https://doi.org/10.1054/drup.2000.0146
doi: 10.1054/drup.2000.0146
Sköld O (2001) Resistance to trimethoprim and sulfonamides. Vet Res 32(3–4):261–273. https://doi.org/10.1051/vetres:2001123
doi: 10.1051/vetres:2001123
pubmed: 11432417
Swedberg G, Ringertz S, Sköld O (1998) Sulfonamide resistance in Streptococcus pyogenes is associated with differences in the amino acid sequence of its chromosomal dihydropteroate synthase. Antimicrob Agents Chemother 42(5):1062–1067. https://doi.org/10.1128/AAC.42.5.1062
doi: 10.1128/AAC.42.5.1062
pubmed: 9593127
pmcid: 105745
Tran TQ, Park M, Lee JE, Kim SH, Jeong JH, Choy HE (2023) Analysis of antibiotic resistance gene cassettes in a newly identified Salmonella enterica serovar Gallinarum strain in Korea. Mob DNA 14(1):4. https://doi.org/10.1186/s13100-023-00292-8
doi: 10.1186/s13100-023-00292-8
pubmed: 37095552
pmcid: 10124037
Wang P, Lee CS, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins WM, Sims PF, Hyde JE (1997) Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Mol Biochem Parasitol 89(2):161–177. https://doi.org/10.1016/s0166-6851(97)00114-x
doi: 10.1016/s0166-6851(97)00114-x
pubmed: 9364963
Yun MK, Wu YLZ, Zhao Y, Waddell MB, Ferreira AM, Lee RE, Bashford D, White SW (2012) Catalysis and sulfa drug resistance in dihydropteroate synthase. Science (new York, n.y.) 335(6072):1110–1114. https://doi.org/10.1126/science.1214641
doi: 10.1126/science.1214641
pubmed: 22383850