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Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.

ABSTRACT: Implant-associated infections (IAIs) caused by S. aureus can result in serious challenges after orthopedic surgery. Due to biofilm formation and antibiotic resistance, this refractory infection is highly prevalent, and finding drugs to attenuate bacterial virulence is becoming a rational alternative strategy. In S. aureus, the SaeRS two-component system (TCS) plays a key role in the production of over 20 virulence factors and the pathogenesis of the bacterium. Here, by conducting a structure-based virtual screening against SaeR, we identified that fenoprofen, a USA Food and Drug Administration (FDA)-approved nonsteroid anti-inflammatory drug (NSAID), had excellent inhibitory potency against the response regulator SaeR protein. We showed that fenoprofen attenuated the virulence of S. aureus without drug resistance. In addition, it was helpful in relieving osteolysis and restoring the walking ability of mice in vitro and in implant-associated infection models. More importantly, fenoprofen treatment suppressed biofilm formation and changed the biofilm structure, which caused S. aureus to form loose and porous biofilms that were more vulnerable to infiltration and elimination by leukocytes. Our results reveal that fenoprofen is a potent antivirulence agent with potential value in clinical applications and that SaeR is a drug target against S. aureus implant-associated infections.

SUBMITTER: Jiang F

PROVIDER: S-EPMC10375895 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.

Jiang Feng F Chen Yingjia Y Yu Jinlong J Zhang Feiyang F Liu Qian Q He Lei L Musha Hamushan H Du Jiafei J Wang Boyong B Han Pei P Chen Xiaohua X Tang Jin J Li Min M Shen Hao H

ACS central science 20230615 7

Implant-associated infections (IAIs) caused by S. aureus can result in serious challenges after orthopedic surgery. Due to biofilm formation and antibiotic resistance, this refractory infection is highly prevalent, and finding drugs to attenuate bacterial virulence is becoming a rational alternative strategy. In S. aureus, the SaeRS two-component system (TCS) plays a key role in the production of over 20 virulence factors and the pathogenesis of the bacterium. Here, by conducting a ...[more]

PMID: 37521790

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Project description:Clinical isolates of Staphylococcus aureus can express biofilm phenotypes promoted by the major cell wall autolysin and the fibronectin-binding proteins or the icaADBC-encoded polysaccharide intercellular adhesin/poly-N-acetylglucosamine (PIA/PNAG). Biofilm production in methicillin-susceptible S. aureus (MSSA) strains is typically dependent on PIA/PNAG whereas methicillin-resistant isolates express an Atl/FnBP-mediated biofilm phenotype suggesting a relationship between susceptibility to ?-lactam antibiotics and biofilm. By introducing the methicillin resistance gene mecA into the PNAG-producing laboratory strain 8325-4 we generated a heterogeneously resistant (HeR) strain, from which a homogeneous, high-level resistant (HoR) derivative was isolated following exposure to oxacillin. The HoR phenotype was associated with a R???H substitution in the DHHA1 domain of GdpP, a recently identified c-di-AMP phosphodiesterase with roles in resistance/tolerance to ?-lactam antibiotics and cell envelope stress. Transcription of icaADBC and PNAG production were impaired in the 8325-4 HoR derivative, which instead produced a proteinaceous biofilm that was significantly inhibited by antibodies against the mecA-encoded penicillin binding protein 2a (PBP2a). Conversely excision of the SCCmec element in the MRSA strain BH1CC resulted in oxacillin susceptibility and reduced biofilm production, both of which were complemented by mecA alone. Transcriptional activity of the accessory gene regulator locus was also repressed in the 8325-4 HoR strain, which in turn was accompanied by reduced protease production and significantly reduced virulence in a mouse model of device infection. Thus, homogeneous methicillin resistance has the potential to affect agr- and icaADBC-mediated phenotypes, including altered biofilm expression and virulence, which together are consistent with the adaptation of healthcare-associated MRSA strains to the antibiotic-rich hospital environment in which they are frequently responsible for device-related infections in immuno-compromised patients.

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Repurposed Fenoprofen Targeting SaeR Attenuates Staphylococcus aureus Virulence in Implant-Associated Infections.

Publications

Repurposed Fenoprofen Targeting SaeR Attenuates <i>Staphylococcus aureus</i> Virulence in Implant-Associated Infections.

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