The β-Lactamase Inhibitor Boronic Acid Derivative SM23 as a New Anti-Pseudomonas aeruginosa Biofilm

Abstract

Pseudomonas aeruginosa is a Gram-negative nosocomial pathogen, often causative agent of severe device-related infections, given its great capacity to form biofilm. P. aeruginosa finely regulates the expression of numerous virulence factors, including biofilm production, by Quorum Sensing (QS), a cell-to-cell communication mechanism used by many bacteria. Selective inhibition of QS-controlled pathogenicity without affecting bacterial growth may represent a novel promising strategy to overcome the well-known and widespread drug resistance of P. aeruginosa. In this study, we investigated the effects of SM23, a boronic acid derivate specifically designed as β-lactamase inhibitor, on biofilm formation and virulence factors production by P. aeruginosa. Our results indicated that SM23: (1) inhibited biofilm development and production of several virulence factors, such as pyoverdine, elastase, and pyocyanin, without affecting bacterial growth; (2) decreased the levels of 3-oxo-C 12-HSL and C 4-HSL, two QS-related autoinducer molecules, in line with a dampened lasR/lasI system; (3) failed to bind to bacterial cells that had been preincubated with P. aeruginosa-conditioned medium; and (4) reduced both biofilm formation and pyoverdine production by P. aeruginosa onto endotracheal tubes, as assessed by a new in vitro model closely mimicking clinical settings. Taken together, our results indicate that, besides inhibiting β-lactamase, SM23 can also act as powerful inhibitor of P. aeruginosa biofilm, suggesting that it may have a potential application in the prevention and treatment of biofilm-associated P. aeruginosa infections.

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

“…Bacteria resistance can usually be associated with the overexpression of different classes of β-lactamases by Gram negative bacteria, and the design of novel potential inhibitors of this enzyme is a very useful strategy. A well-known example of a β-lactamase inhibitor is the clavulanic acid [ 2 , 58 , 59 , 60 , 61 ]. The first report that boronic acids could act as β-lactamase inhibitors was made by a research group from Oxford University that noticed that borate ions inhibit β-lactamase I [ 62 ].…”

“…Specific interactions with various β-lactamases can be reached through introduction of different chemical groups on the carbon that carries the boronic acid group, providing an inhibitory activity in a precise manner for the different types of these enzymes. Because of these characteristics, studies about selective and potent boronic acid compounds are being made to discover novel compounds that can be administrated in combination with a β-lactam antibiotic agent [ 1 , 58 , 60 , 64 , 65 ].…”

“…This compound is also a BATSI and is considered as one of the best inhibitors of class C β-lactamases reported to date. Its design was based on the mimetic approach, in which the different chemical groups with a suitable stereochemistry were arranged with a boronic acid in order to resemble the natural substrate β-lactam [ 60 , 64 ]. SAR studies revealed that the introduction of a group with negative charge in the side chain, such as a carboxylate, improves binding affinity and cell penetration and that one of the hydroxyl groups of boronic acid is important to form an interaction with the nitrogen of serine residues (Ser64 and Ser315) in the oxyanion hole of the active site of β-lactamases [ 64 ].…”

“…A recent publication revealed another interesting application of compound 72 as an inhibitor of the formation of biofilms by Pseudomonas aeruginosa, a Gram-negative bacteria that is responsible for many nosocomial infections in immunosuppressive patients and is very resistant. When exposed to SM23 ( 72 ), it is observed inhibition in the production of virulence factors related to the formation of biofilms of P. aeruginosa , like pyoverdine and elastase, without co-administration of an antibiotic [ 60 ].…”

Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function

“…In addition, pyoverdine is druggable; there have been multiple reports describing small molecules targeting either pyoverdine itself or its biosynthesis [9,12,[26][27][28][29][30][31][32]. As it is a siderophore, pyoverdine is naturally secreted from bacteria at high levels and it is readily soluble in water.…”