Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus
Abstract
:1. Introduction
2. Results
2.1. Compounds and Chemistry
2.2. Antimicrobial Activity
2.3. Synergistic Study
2.4. Molecular Analysis
2.5. Cytotoxicity Studies
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Synthesis
4.2.1. Synthetic Procedures for Nitriles 1n and 1o
4.2.2. General Synthetic Procedures for Amidoximes 2a-o
4.2.3. Synthetic procedures for compounds 3–17
4.3. Antibiotics and Strains
4.4. Antimicrobial Susceptibility Testing
4.5. Killing Rate
4.6. Checkerboard Method
4.7. Molecular Analysis
4.8. Bioscreens In Vitro for Cytotoxicity Studies
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Tong, S.Y.; Davis, J.S.; Eichenberger, E.; Holland, T.L.; Fowler, V.G., Jr. Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin. Microbiol. Rev. 2015, 28, 603–661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, S.C.; Liu, F.; Zhu, K.; Shen, J.Z. Natural products that target virulence factors in antibiotic-resistant Staphylococcus aureus. J. Agric. Food Chem. 2019, 67, 13195–13211. [Google Scholar] [CrossRef]
- Gajdács, M. The continuing threat of methicillin-resistant Staphylococcus aureus. Antibiotics 2019, 8, 52. [Google Scholar] [CrossRef] [Green Version]
- Guzzo, F.; Scognamiglio, M.; Fiorentino, A.; Buommino, E.; D’Abrosca, B. Plant derived natural products against Pseudomonas aeruginosa and Staphylococcus aureus: Antibiofilm activity and molecular mechanisms. Molecules 2020, 25, 5024. [Google Scholar] [CrossRef]
- Laupland, K.B.; Lyytikainen, O.; Sogaard, M.; Kennedy, K.J.; Knudsen, J.D.; Ostergaard, C.; Galbraith, J.C.; Valiquette, L.; Jacobsson, G.; Collignon, P.; et al. The changing epidemiology of Staphylococcus aureus bloodstream infection: A multinational population-based surveillance study. Clin. Microbiol. Infect. 2013, 19, 465–471. [Google Scholar] [CrossRef] [Green Version]
- Chambers, H.F.; Deleo, F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat. Rev. Microbiol. 2009, 7, 629–641. [Google Scholar] [CrossRef]
- Dalvie, D.K.; Kalgutkar, A.S.; Khojasteh-Bakht, S.C.; Obach, R.S.; O’Donnell, J.P. Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem. Res. Toxicol. 2002, 15, 269–299. [Google Scholar] [CrossRef]
- Biernacki, K.; Daśko, M.; Ciupak, O.; Kubiński, K.; Rachon, J.; Demkowicz, S. Novel 1,2,4-oxadiazole derivatives in drug discovery. Pharmaceuticals 2020, 13, 111. [Google Scholar] [CrossRef]
- Chawla, G. 1,2,4-Oxadiazole as a privileged scaffold for anti-inflammatory and analgesic activities: A review. Mini Rev. Med. Chem. 2018, 18, 1536–1547. [Google Scholar] [CrossRef] [PubMed]
- Ceballos, S.; Kim, C.; Ding, D.; Mobashery, S.; Chang, M.; Torresa, C. Activities of oxadiazole antibacterials against Staphylococcus aureus and other gram-positive bacteria. Antimicrob. Agents Chemother. 2018, 62, e00453-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- O’Daniel, P.I.; Pi, Z.P.H.; Testero, S.A.; Ding, D.; Spink, E.; Leemans, E.; Boudreau, M.A.; Yamaguchi, T.; Schroeder, V.A.; Wolter, W.R.; et al. Discovery of a new class of non-β-lactam inhibitors of penicillin binding proteins with Gram-Positive antibacterial activity. J. Am. Chem. Soc. 2014, 136, 3664–3672. [Google Scholar] [CrossRef]
- Spink, E.; Ding, D.; Peng, Z.; Boudreau, M.A.; Leemans, E.; Lastochkin, E.; Song, W.; Lichtenwalter, K.; O’Daniel, P.I.; Testero, S.A.; et al. Structure−activity relationship for the oxadiazole class of antibiotics. J. Med. Chem. 2015, 58, 1380–1389. [Google Scholar] [CrossRef]
- Boudreau, M.A.; Ding, D.; Meisel, J.E.; Janardhanan, J.; Spink, E.; Peng, Z.; Qian, Y.; Yamaguchi, T.; Testero, S.A.; O’Daniel, P.I.; et al. Structure–Activity relationship for the oxadiazole class of antibacterials. ACS Med. Chem. Lett. 2020, 11, 322–326. [Google Scholar] [CrossRef]
- Ding, D.; Boudreau, M.A.; Leemans, E.; Spink, E.; Yamaguchi, T.; Testero, S.A.; O’Daniel, P.I.; Lastochkin, E.; Chang, M. Mobashery, S. Exploration of the structure-activity relationship of 1,2,4-oxadiazole antibiotics. Bioorg. Med. Chem. Lett. 2015, 25, 4854–4857. [Google Scholar] [CrossRef] [Green Version]
- Di Leva, F.S.; Festa, C.; Carino, A.; De Marino, S.; Marchianò, S.; Di Marino, D.; Finamore, C.; Monti, M.C.; Zampella, A.; Fiorucci, S.; et al. Discovery of ((1,2,4-oxadiazol-5-yl) pyrrolidin-3-yl)ureidyl derivatives as selective non-steroidal agonists of the G-protein coupled bile acid receptor-1. Sci. Rep. 2019, 9, 2504. [Google Scholar] [CrossRef] [PubMed]
- Festa, C.; Finamore, C.; Marchiano, S.; Di Leva, F.S.; Carino, A.; Monti, M.C.; del Gaudio, F.; Ceccacci, S.; Limongelli, V.; Zampella, A.; et al. Investigation around the oxadiazole core in the discovery of a new chemotype of potent and selective FXR antagonists. ACS Med. Chem. Lett. 2019, 10, 504–510. [Google Scholar] [CrossRef] [PubMed]
- Potenza, M.; Sciarretta, M.; Chini, M.G.; Saviano, A.; Maione, F.; D’Auria, M.V.; De Marino, S.; Giordano, A.; Hofstetter, R.K.; Festa, C.; et al. Structure-based screening for the discovery of 1,2,4-oxadiazoles as promising hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways. Eur. J. Med. Chem. 2021, 224, 113693. [Google Scholar] [CrossRef] [PubMed]
- Sharma, K.K.; Maurya, I.K.; Khan, S.I.; Jacob, M.R.; Kumar, V.; Tikoo, K.; Jain, R. Discovery of a membrane-active, ring-modified histidine containing ultrashort amphiphilic peptide that exhibits potent inhibition of Cryptococcus neoformans. J. Med. Chem. 2017, 60, 6607–6621. [Google Scholar] [CrossRef] [PubMed]
- Bellavita, R.; Vollaro, A.; Catania, M.R.; Merlino, F.; De Martino, L.; Nocera, F.P.; Della Greca, M.; Lembo, F.; Grieco, P.; Buommino, E. Novel antimicrobial peptide from temporin L in the treatment of Staphylococcus pseudintermedius and Malassezia pachydermatis in polymicrobial inter-kingdom infection. Antibiotics 2020, 9, 530. [Google Scholar] [CrossRef] [PubMed]
- Zarghi, A.; Hajimahdi, Z. Substituted oxadiazoles: A patent review (2010−2012). Expert Opin. Ther. Patents 2013, 23, 1209–1232. [Google Scholar] [CrossRef]
- Pidugu, V.R.; Yarla, N.S.; Pedada, S.R.; Kalle, A.M.; Satya, A.K. Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti-cancer activity. Bioorg. Med. Chem. 2016, 24, 5611–5617. [Google Scholar] [CrossRef] [PubMed]
- Guda, D.R.; Park, S.-J.; Lee, M.-W.; Kim, T.-J.; Lee, M.E. Syntheses and antiallergic activity of 2-((bis(trimethylsilyl)methylthio/methylsulfonyl) methyl)-5-aryl-1,3,4-oxadiazoles. Eur. J. Med. Chem. 2013, 62, 84–88. [Google Scholar] [CrossRef] [PubMed]
- Janardhanan, J.; Chang, M.; Mobashery, S. The oxadiazole antibacterials. Curr. Opin. Microbiol. 2016, 33, 13–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laws, M.; Shaaban, A.; Rahman, K.M. Antibiotic resistance breakers: Current approaches and future directions. FEMS Microbiol. Rev. 2019, 43, 490–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ha, D.R.; Haste, N.M.; Gluckstein, D.P. The role of antibiotic stewardship in promoting appropriate antibiotic use. Am. J. Lifestyle Med. 2017, 13, 376–383. [Google Scholar] [CrossRef]
- Katayama, Y.; Ito, T.; Hiramatsu, K. A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 2000, 44, 1549–1555. [Google Scholar] [CrossRef] [Green Version]
- Liu, J.; Chen, D.; Peters, B.M.; Li, L.; Li, B.; Xu, Z.; Shirliff, M.E. Staphylococcal chromosomal cassettes mec (SCCmec): A mobile genetic element in methicillin-resistant Staphylococcus aureus. Microb. Pathog. 2016, 101, 56–67. [Google Scholar] [CrossRef] [PubMed]
- Rudkin, J.K.; Laabei, M.; Edwards, A.M.; Joo, H.S.; Otto, M.; Lennon, K.L.; O’Gara, J.P.; Waterfield, N.R.; Massey, R.C. Oxacillin alters the toxin expression profile of community-associated methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2014, 58, 1100–1107. [Google Scholar] [CrossRef] [Green Version]
- Bellavita, R.; Falanga, A.; Buommino, E.; Merlino, F.; Casciaro, B.; Cappiello, F.; Mangoni, M.L.; Novellino, E.; Catania, M.R.; Paolillo, R.; et al. Novel temporin L antimicrobial peptides: Promoting self-assembling by lipidic tags to tackle superbugs. J. Enzyme Inhib. Med. Chem. 2020, 35, 1751–1764. [Google Scholar] [CrossRef]
- Olajuyigbe, O.O.; Afolayan, A.J. In vitro antibacterial and time- kill evaluation of the Erythrina caffra thunb. extract against bacteria associated with diarrhea. Sci. World J. 2012, 2012, 738314. [Google Scholar] [CrossRef] [Green Version]
- Yap, J.K.Y.; Tan, S.Y.Y.; Tang, S.Q.; Thien, V.K.; Chan, E.W.L. Synergistic antibacterial activity between 1,4-naphthoquinone and β-lactam antibiotics against methicillin-resistant Staphylococcus aureus. Microb. Drug Resist. 2021, 27, 234–240. [Google Scholar] [CrossRef] [PubMed]
- Irace, C.; Misso, G.; Capuozzo, A.; Piccolo, M.; Riccardi, C.; Luchini, A.; Caraglia, M.; Paduano, L.; Montesarchio, D.; Santamaria, R. Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: Insights into their mode of action. Sci. Rep. 2017, 7, 45236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cmpds | R1 | S. aureus ATCC 29213 | S. aureus ATCC 43300 |
---|---|---|---|
3 | 4 | 4 | |
4 | >100 | >100 | |
5 | 25 | 12.5 | |
6 | 6.25 | 6.25 | |
7 | 100 | 100 | |
8 | >100 | >100 | |
9 | 25 | 25 | |
10 | >100 | >100 | |
11 | 6.25 | 6.25 | |
12 | 2 | 2 | |
13 | 6.25 | 6.25 | |
14 | 6.25 | 6.25 | |
15 | 12.5 | 12.5 | |
16 | >100 | >100 | |
17 | >100 | >100 | |
Vancomycin a | 2 | 2 | |
Oxacillin a | 2 | 10 |
Gene | Sense and Antisense Sequences | Conditions | bp |
---|---|---|---|
mecA | 5′–TCCACCCTCAAACAGGTGAA-3′ 5′-TGGAACTTGTTGAGCAGAGGT-3′ | 95 °C for 5′ 94 °C for 30′’, 55 °C for 30′’, 72 °C for 30′’ for 33 cycles 72 °C for 7′ | 139 |
mecI | 5′-TCATCTGCAGAATGGGAAGTT-3′ 5′-TTGGACTCCAGTCCTTTTGC-3′ | 103 | |
mecR1 | 5′-AGCACCGTTACTATCTGCACA-3′ 5′-AGAATAAGCTTGCTCCCGTTCA-3′ | 142 | |
rRNA16S | 5′-CGGTCCAGACTCCTACGGGAGGCAGCA-3′ 5′-GCGTGGACTACCAGGGTATCTAATCC-3′ | 450 |
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Buommino, E.; De Marino, S.; Sciarretta, M.; Piccolo, M.; Festa, C.; D’Auria, M.V. Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus. Antibiotics 2021, 10, 1258. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10101258
Buommino E, De Marino S, Sciarretta M, Piccolo M, Festa C, D’Auria MV. Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus. Antibiotics. 2021; 10(10):1258. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10101258
Chicago/Turabian StyleBuommino, Elisabetta, Simona De Marino, Martina Sciarretta, Marialuisa Piccolo, Carmen Festa, and Maria Valeria D’Auria. 2021. "Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus" Antibiotics 10, no. 10: 1258. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10101258