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.
Highlights
Staphylococcus aureus is a gram-positive bacterium that can cause life-threatening community-acquired and nosocomial-associated infections
Methicillin-resistant S. aureus (MRSA), which is resistant to β-lactam antibiotics such as penicillins, cephalosporins, and carbapenems, is among the most widely distributed drug-resistant bacterial species worldwide
Resistance to methicillin is primarily conferred by the acquisition of mecA, which encodes penicillinbinding protein 2a (PBP2a), which has a low affinity for β-lactam antibiotics.[1]
Summary
Staphylococcus aureus is a gram-positive bacterium that can cause life-threatening community-acquired and nosocomial-associated infections. Methicillin-resistant S. aureus (MRSA), which is resistant to β-lactam antibiotics such as penicillins, cephalosporins, and carbapenems, is among the most widely distributed drug-resistant bacterial species worldwide. Resistance to methicillin is primarily conferred by the acquisition of mecA, which encodes penicillinbinding protein 2a (PBP2a), which has a low affinity for β-lactam antibiotics.[1] In the United States, 19,000 hospitalized patients die annually because of MRSA infections.[2]. Cells in the biofilm are embedded in an extracellular matrix (ECM) comprising extracellular DNA, proteins, and polysaccharide intercellular adhesin (PIA).[3] Biofilm cells are more resistant to antibiotics than planktonic cells because their metabolic activity is lower, and cell division, which is required for sensitivity to many antibiotics, is markedly attenuated.[4, 5] biofilm cells can withstand exposure to antibiotics at concentrations up to 1000-fold higher than those required to inhibit the growth of planktonic cells.[6]
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