Multisubstituted Pyrimidines Effectively Inhibit Bacterial Growth and Biofilm Formation of Staphylococcus Aureus

Overview

Journal Sci Rep

Specialty Science

Date 2021 Apr 13

PMID 33846401

Citations 8

Authors

Riccardo Provenzani

Paola San-Martin-Galindo

Ghada Hassan

Ashenafi Legehar

Aleksi Kallio

Henri Xhaard

Adyary Fallarero

Jari Yli-Kauhaluoma

Affiliations

Soon will be listed here.

Abstract

Biofilms are multicellular communities of microorganisms that generally attach to surfaces in a self-produced matrix. Unlike planktonic cells, biofilms can withstand conventional antibiotics, causing significant challenges in the healthcare system. Currently, new chemical entities are urgently needed to develop novel anti-biofilm agents. In this study, we designed and synthesized a set of 2,4,5,6-tetrasubstituted pyrimidines and assessed their antibacterial activity against planktonic cells and biofilms formed by Staphylococcus aureus. Compounds 9e, 10d, and 10e displayed potent activity for inhibiting the onset of biofilm formation as well as for killing pre-formed biofilms of S. aureus ATCC 25923 and Newman strains, with half-maximal inhibitory concentration (IC) values ranging from 11.6 to 62.0 µM. These pyrimidines, at 100 µM, not only decreased the number of viable bacteria within the pre-formed biofilm by 2-3 log but also reduced the amount of total biomass by 30-50%. Furthermore, these compounds were effective against planktonic cells with minimum inhibitory concentration (MIC) values lower than 60 µM for both staphylococcal strains. Compound 10d inhibited the growth of S. aureus ATCC 25923 in a concentration-dependent manner and displayed a bactericidal anti-staphylococcal activity. Taken together, our study highlights the value of multisubstituted pyrimidines to develop novel anti-biofilm agents.

Citing Articles

Characterization of an Acetogenin-Carrying Nanosuspension and Its Effect on Bacteria of Interest in the Poultry Industry.

Lopez-Romero B, Aguilar-Hernandez G, Hargis B, de Lourdes Garcia-Magana M, Lopez-Garcia U, Ortiz-Basurto R Microorganisms. 2025; 13(1).

PMID: 39858786 PMC: 11768020. DOI: 10.3390/microorganisms13010018.

Antibiofilm Activities of Multiple Halogenated Pyrimidines Against .

Sim M, Kim Y, Lee J, Lee J Int J Mol Sci. 2024; 25(23).

PMID: 39684543 PMC: 11641129. DOI: 10.3390/ijms252312830.

Design, synthesis, inhibitory activity, and molecular simulations study for d-glucose-conjugated thioureas containing pyrimidine ring as multitarget inhibitors against α-amylase, α-glucosidase, DDP-4, and PTP1B in Type 2 diabetes mellitus.

Toan V, Son Hai D, Thi Kim Van H, Minh Tri N, Ngoc Toan D, Thi Thanh Mai N RSC Med Chem. 2024; .

PMID: 39185455 PMC: 11342126. DOI: 10.1039/d4md00334a.

Fluoropyrimidines affect pyrimidine synthesis impairing biofilm formation in .

Ravishankar S, Baldelli V, Angeletti C, Raffaelli N, Landini P, Rossi E Biofilm. 2024; 7:100180.

PMID: 38370152 PMC: 10869245. DOI: 10.1016/j.bioflm.2024.100180.

Protective Effect of Procyanidin-Rich Grape Seed Extract against Gram-Negative Virulence Factors.

Nicolosi R, Bonincontro G, Imperia E, Badiali C, De Vita D, Sciubba F Antibiotics (Basel). 2023; 12(11).

PMID: 37998817 PMC: 10668874. DOI: 10.3390/antibiotics12111615.

References

Otto M . Staphylococcal infections: mechanisms of biofilm maturation and detachment as critical determinants of pathogenicity. Annu Rev Med. 2012; 64:175-88. DOI: 10.1146/annurev-med-042711-140023. View

Sandberg M, Maattanen A, Peltonen J, Vuorela P, Fallarero A . Automating a 96-well microtitre plate model for Staphylococcus aureus biofilms: an approach to screening of natural antimicrobial compounds. Int J Antimicrob Agents. 2008; 32(3):233-40. DOI: 10.1016/j.ijantimicag.2008.04.022. View

Manner S, Goeres D, Skogman M, Vuorela P, Fallarero A . Prevention of Staphylococcus aureus biofilm formation by antibiotics in 96-Microtiter Well Plates and Drip Flow Reactors: critical factors influencing outcomes. Sci Rep. 2017; 7:43854. PMC: 5333151. DOI: 10.1038/srep43854. View

POWERS J . Antimicrobial drug development--the past, the present, and the future. Clin Microbiol Infect. 2004; 10 Suppl 4:23-31. DOI: 10.1111/j.1465-0691.2004.1007.x. View

Arciola C, Campoccia D, Ravaioli S, Montanaro L . Polysaccharide intercellular adhesin in biofilm: structural and regulatory aspects. Front Cell Infect Microbiol. 2015; 5:7. PMC: 4322838. DOI: 10.3389/fcimb.2015.00007. View

Johar M, Manning T, Kunimoto D, Kumar R . Synthesis and in vitro anti-mycobacterial activity of 5-substituted pyrimidine nucleosides. Bioorg Med Chem. 2005; 13(24):6663-71. DOI: 10.1016/j.bmc.2005.07.046. View

Coates A, Hu Y . Novel approaches to developing new antibiotics for bacterial infections. Br J Pharmacol. 2007; 152(8):1147-54. PMC: 2189988. DOI: 10.1038/sj.bjp.0707432. View

Bartlett J, Gilbert D, Spellberg B . Seven ways to preserve the miracle of antibiotics. Clin Infect Dis. 2013; 56(10):1445-50. DOI: 10.1093/cid/cit070. View

Romling U, Balsalobre C . Biofilm infections, their resilience to therapy and innovative treatment strategies. J Intern Med. 2012; 272(6):541-61. DOI: 10.1111/joim.12004. View

10.

Manner S, Vahermo M, Skogman M, Krogerus S, Vuorela P, Yli-Kauhaluoma J . New derivatives of dehydroabietic acid target planktonic and biofilm bacteria in Staphylococcus aureus and effectively disrupt bacterial membrane integrity. Eur J Med Chem. 2015; 102:68-79. DOI: 10.1016/j.ejmech.2015.07.038. View

11.

Fontaine F, Hequet A, Voisin-Chiret A, Bouillon A, Lesnard A, Cresteil T . Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives. Eur J Med Chem. 2015; 95:185-98. DOI: 10.1016/j.ejmech.2015.02.056. View

12.

Mendez D, Gaulton A, Bento A, Chambers J, de Veij M, Felix E . ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res. 2018; 47(D1):D930-D940. PMC: 6323927. DOI: 10.1093/nar/gky1075. View

13.

Fallarero A, Skogman M, Kujala J, Rajaratnam M, Moreira V, Yli-Kauhaluoma J . (+)-Dehydroabietic acid, an abietane-type diterpene, inhibits Staphylococcus aureus biofilms in vitro. Int J Mol Sci. 2013; 14(6):12054-72. PMC: 3709773. DOI: 10.3390/ijms140612054. View

14.

Bryers J . Medical biofilms. Biotechnol Bioeng. 2008; 100(1):1-18. PMC: 2706312. DOI: 10.1002/bit.21838. View

15.

Rahman M, Shiu W, Gibbons S, Malkinson J . Total synthesis of acylphloroglucinols and their antibacterial activities against clinical isolates of multi-drug resistant (MDR) and methicillin-resistant strains of Staphylococcus aureus. Eur J Med Chem. 2018; 155:255-262. DOI: 10.1016/j.ejmech.2018.05.038. View

16.

Yarinich L, Burakova E, Zakharov B, Boldyreva E, Babkina I, Tikunova N . Synthesis and structure-activity relationship of novel 1,4-diazabicyclo[2.2.2]octane derivatives as potent antimicrobial agents. Eur J Med Chem. 2015; 95:563-73. DOI: 10.1016/j.ejmech.2015.03.033. View

17.

Levison M . Pharmacodynamics of antimicrobial drugs. Infect Dis Clin North Am. 2004; 18(3):451-65, vii. DOI: 10.1016/j.idc.2004.04.012. View

18.

Pitts B, Hamilton M, Zelver N, Stewart P . A microtiter-plate screening method for biofilm disinfection and removal. J Microbiol Methods. 2003; 54(2):269-76. DOI: 10.1016/s0167-7012(03)00034-4. View

19.

Peeters E, Nelis H, Coenye T . Comparison of multiple methods for quantification of microbial biofilms grown in microtiter plates. J Microbiol Methods. 2007; 72(2):157-65. DOI: 10.1016/j.mimet.2007.11.010. View

20.

Kropec A, Maira-Litran T, Jefferson K, Grout M, Cramton S, Gotz F . Poly-N-acetylglucosamine production in Staphylococcus aureus is essential for virulence in murine models of systemic infection. Infect Immun. 2005; 73(10):6868-76. PMC: 1230935. DOI: 10.1128/IAI.73.10.6868-6876.2005. View