Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics

Abstract

Formation of bacterial biofilms on medical devices can cause severe or fatal infectious diseases. In particular, biofilm-associated infections caused by methicillin-resistant Staphylococcus aureus are difficult to eradicate because the biofilm is strongly resistant to antibiotics and the host immune response. There is no effective treatment for biofilm-associated infectionss, except for surgical removal of contaminated medical devices followed by antibiotic therapy. Here we show that norgestimate, an acetylated progestin, effectively inhibits biofilm formation by staphylococcal strains, including methicillin-resistant S. aureus, without inhibiting their growth, decreasing the selective pressure for emergence of resistance. 17-Deacetyl norgestimate, a metabolite of norgestimate, shows much weaker inhibitory activity against staphylococcal biofilm formation, indicating that the acetyl group of norgestimate is important for its activity. Norgestimate inhibits staphylococcal biofilm formation by inhibiting production of polysaccharide intercellular adhesin and proteins in the extracellular matrix. Proteome analysis of S. aureus indicated that norgestimate represses the expression of the cell wall-anchored protein SasG, which promotes intercellular adhesion, and of the glycolytic enzyme enolase, which plays a secondary role in biofilm formation. Notably, norgestimate induces remarkable changes in cell wall morphology, characterized by increased thickness and abnormal rippled septa. Furthermore, norgestimate increases the expression level of penicillin binding protein 2 and resensitizes methicillin-resistant S. aureus to β-lactam antibiotics. These results suggest that norgestimate is a promising lead compound for the development of drugs to treat biofilm-associated infections, as well as for its ability to resensitize methicillin-resistant S. aureus to β-lactam antibiotics.

Secondary Effects of Antibiotics on Microbial Biofilms

“… Yoshii et al (2017) have shown that norgestimate, a compound primarily used for oral contraception and hormone replacement therapy ( Henzl, 2001 ) but also investigated as a potential antibiofilm/antibiotic agent, was able to inhibit biofilm formation by staphylococcal strains. It did so via inhibiting production of a polysaccharide adhesin and proteins in the extracellular matrix, thus affecting biofilm structure and integrity ( Yoshii et al, 2017 ).…”

Egyptian fennel honey and/or propolis against MRSA harboring both mecA & icaAgenes

“…MRSA biofilm-associated infections are difficult to be eradicated because the biofilm is strongly resistant to wide variety of antibiotics and the host immune response. 3 The vast majority of food-borne outbreaks caused by antimicrobial-resistant pathogens are the result of the consumption of contaminated foods of either animal-origin or multi-ingredient foods. 42 In the present study, MAR index among food strains, MRSA from meat showed the highest value as 0.61±0.1 (Figure 1), while among food worker strains, fingernail strains showed 0.57±0.14.…”

“…1 MRSA resists β-lactams antibiotics (penicillins, cephalosporins, monobactams, and carbapenems groups) 2 which are primarily conferred by the acquisition of mecA gene encoding penicillin binding protein (PBP 2a). 3 This protein is an important factor in biofilm accumulation, 4 then MRSA adhere to biotic or abiotic surfaces 5 and be protected against hostile environments. 6 MRSA antimicrobial resistance might be increased on harbouring any of biofilm producing gene (ica operon).…”

During the Early Stages of Staphylococcus aureus Biofilm Formation, Induced Neutrophil Extracellular Traps Are Degraded by Autologous Thermonuclease

“…Analysis of biofilm composition formed in IMDM and TSB revealed that, indeed, after 4 h of growth, very minimal amounts of eDNA were seen in any of the biofilms. However, biofilms formed in IMDM did contain N-acetylglucosamine-containing components, presumably PIA, which was visualized by wheat germ agglutinin (WGA) lectin staining (39). After 24 h of growth, dead cells and eDNA were observed in biofilms grown in TSB but not biofilms grown in IMDM.…”