Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN)

Abstract

Antivirulence strategies are now attracting interest for the inherent mechanism of action advantages. In our previous work, diapophytoene desaturase (CrtN) was identified to be an attractive and drugable target for fighting pigmented S. aureus infections. In this research, we developed a series of effective benzocycloalkane-derived CrtN inhibitors with submicromolar IC50. Analogue 8 blocked the pigment biosynthesis of three MRSA strains with a nanomolar IC50 value. Corresponding to its mode of action, 8 did not function as a bactericidal agent. 8 could sensitize S. aureus to immune clearance. In vivo, 8 was proven to be efficacious in an S. aureus Newman sepsis model and abscess formation model. For two typical MRSAs, USA400 MW2 and Mu50, 8 significantly decreased the staphylococcal loads in the liver and kidneys. Moreover, 8 showed minimal antifungal activity compared to that of NTF. In summary, 8 has the potential to be developed as a therapeutic drug, especially against intractable MRSA issues.

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

“…In parallel, to further explore the potency of 19 and expand upon efficient novel inhibitors with independent intellectual property rights, we started another design of 19 ‐derived CrtN inhibitors . On the basis of the discovery of benzofuran analogs and their SAR, we confirmed that the naphthyl group in 19 or its similar groups, such as benzofuran, was necessary for maintaining pigment inhibition by blocking the enzyme CrtN.…”

“…In parallel, to further explore the potency of 19 and expand upon efficient novel inhibitors with independent intellectual property rights, we started another design of 19-derived CrtN inhibitors. 91 On the basis of the discovery of benzofuran analogs and their SAR, we confirmed that the naphthyl group in 19 or its similar groups, such as benzofuran, was necessary for maintaining pigment inhibition by blocking the enzyme CrtN. Rather than replacing the naphthyl group of 19 with various heteroaromatic groups, we initially intended to switch the naphthyl moiety of 19 into some benzocycloalkane rings of different sizes to generate novel skeleton compounds, which resulted in the synthesis of the derivatives 30-32.…”

Identification and characterization of potential membrane-bound molecular drug targets of methicillin-resistant Staphylococcus aureus using in silico approaches

“…Today, a number of proteins are considered as promising drug targets for the development of antibiotics to treat staphylococcal infections. After extensive review of the literature for the last three years, the following proteins were considered as potential therapeutic drug targets for the development of antistaphylococcal agents: bacterial enoyl reductase (FabI) [3,4], transglycosylase (TGase) [5,6], sortase A [7][8][9][10][11][12][13], diapophytoene desaturase (CrtN) [14][15][16][17], type II topoisomerase [18][19][20][21], topoisomerase IV [22][23][24][25][26][27], filamentous temperature-sensitive protein Z (FtsZ) [28][29][30], UDP-N-acetylenolpyruvylglucosamine reductase (MurB) [31], lipoteichoic acid synthase (LtaS) [32], biotin protein ligase [33,34], peptide deformylase [35], Ser/Thr protein kinase STK1 [36], pentaerythritol tetranintrate reductase [37], peptide deformylase (PDF) [38,39], NorA efflux pump [40][41][42][43][44]…”

Novel Staphyloxanthin Inhibitors with Improved Potency against Multidrug Resistant Staphylococcus aureus

“…19 On the basis of the results above, we further designed and synthesized a series of novel benzofuran and benzocycloalkane CrtN inhibitors, from which the efficient derivatives 3 and 4 were obtained (Figure 1). 20,21 Moreover, analogue 4a displayed excellent potency in vitro (pigment inhibition: IC 50 = 1.9 nM, Figure 1) but was still limited by its strong inhibition of human Ether-a-go-go Related Gene (hERG), high required dosage, and moderate water solubility in subsequent investigations. 21 Therefore, in this study, a novel compound was designed and synthesized to overcome the defects of lead compound 4a.…”

“…20,21 Moreover, analogue 4a displayed excellent potency in vitro (pigment inhibition: IC 50 = 1.9 nM, Figure 1) but was still limited by its strong inhibition of human Ether-a-go-go Related Gene (hERG), high required dosage, and moderate water solubility in subsequent investigations. 21 Therefore, in this study, a novel compound was designed and synthesized to overcome the defects of lead compound 4a. In addition, variable administrations and dosages were introduced for an actual evaluation of the efficiency of our new compounds against multidrug resistant S. aureus in vivo.…”