Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA

Abstract

Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA), the most widespread bacterial pathogen. Structure-activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (1) and aryloxy acetonitriles (2) as synthons. A Lewis-acid-activated Friedel-Crafts' acylation step involving a nitrile functionality of 2 by ZnCl2, followed by nucleophilic attack by 1 was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, 4f-12, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound.

Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens

“…Upon synthesis of a combinatorial library more potent compounds were identified, including biaryl hydroxyketones F12 and F19 (Fig. 2 ) 9 , 10 . F12 is most efficacious in vitro whereas F19 works better in vivo .…”

Thiol activated prodrugs of sulfur dioxide (SO2) as MRSA inhibitors

“…Although efforts to develop new drug candidates with novel mechanisms of action have intensified, the growing number of multidrug resistant MRSA infections has further accentuated the problem of antibiotic resistance necessitating new strategies to target such drug-resistant bacteria. [1][2][3][4][5][6][7] Sulfur dioxide (SO 2 ) is a gaseous environmental pollutant produced during volcanic eruptions and fossil fuel combustion. 8 At elevated levels, SO 2 is toxic to cells and among the various modes for cellular stress induction by SO 2 , perturbation of redox homeostasis through generation of oxidative species has been reported.…”

Novel Quorum-Quenching Agents Promote Methicillin-Resistant Staphylococcus aureus (MRSA) Wound Healing and Sensitize MRSA to β-Lactam Antibiotics

“…In previous work, we have identified small-molecule biaryl hydroxyketone compounds that target the response regulator AgrA and inhibit its interaction with promoter P3, curtailing the production of toxins and virulence factors (8). In a follow-up study, a combinatorial library of 148 compounds was synthesized based on the most efficacious hit compound (9). A member of this biaryl hydroxyketone library, named F12, was the most efficacious of the synthesized compounds, demonstrating 98% in vitro MRSA rabbit erythrocyte hemolysis inhibition at a concentration of 1 g/ml.…”