Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disinteg...Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.展开更多
The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered r...The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)screening was performed in mouse haploid embryonic stem cells infected with pseudorabies virus(PRV),anα-herpesvirus causing human and pig diseases.The results demonstrated that type 2 voltage-gated chloride channels(CLC-2)encoded by one of the identified genes,CLCN2,is a potential drug target for anti-herpesvirus therapy.CLC-2 inhibitors,omeprazole(OME)and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid(DIDS),can efficiently inhibit infection of multiple herpesviruses in cellulo(i.e.,PRV,HSV and EBV),and effectively treat murine herpes simplex encephalitis(HSE).Additionally,DIDS was found to inhibit HSV-1 replication by blocking the PI3K/Akt pathway.Most importantly,both DIDS and OME were able to inhibit ACV-resistant HSV-1 strain infection.The study's findings suggest that targeting host-cell factors such as CLC-2 may be a promising approach to tackling herpesvirus drug resistance.The discovery of CLC-2 as a potential drug target for anti-herpesvirus therapy provides a new direction for the development of novel antiviral agents.展开更多
The emergence of multidrug-resistant bacteria poses a significant challenge in the treatment of osteomyelitis,rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure.In r...The emergence of multidrug-resistant bacteria poses a significant challenge in the treatment of osteomyelitis,rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure.In recent years,triggerable biomaterial-based,antibiotic-free osteomyelitis treatment strategies have rapidly evolved,demonstrating excellent bactericidal effects.Triggerable biomaterials-based osteomyelitis theranostics encompass physical signal response strategies and host immune modulation approaches.These strategies can be effective against drug-resistant bacteria,circumventing the gradual acquisition of resistance that often accompanies traditional antibiotic treat-ment.Additionally,the inherent physical properties of the triggerable bio-materials facilitate the precise imaging of osteomyelitis.There is no doubt that triggerable biomaterial-mediated,antibiotic-free therapies are emerging as a trend,which is critically important in combating multidrug-resistant bacteria-induced osteomyelitis.In this review,we summarize the latest advances in osteomyelitis treatment strategies from both pathogen-directed and host-directed perspectives.The design regimens and specific action mechanisms of triggerable biomaterial-based nanoplatforms are also clarified.Finally,we outline the challenges faced by various antibiotic-free therapies and provide an outlook on the prospects for synergistic interactions.展开更多
基金supported by the National Natural Science Foundation of China(U22A20523,32172912,and 32102722)the Interdisciplinary Integration and Innovation Project of Jilin University(JLUXKJC2021QZ04)。
文摘Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.
基金supported by the National Natural Science Foundation of China(32071443)China Postdoctoral Science Foundation(2023M731465)the Natural Science Foundation of Gansu province(23JRRA1134)。
文摘The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)screening was performed in mouse haploid embryonic stem cells infected with pseudorabies virus(PRV),anα-herpesvirus causing human and pig diseases.The results demonstrated that type 2 voltage-gated chloride channels(CLC-2)encoded by one of the identified genes,CLCN2,is a potential drug target for anti-herpesvirus therapy.CLC-2 inhibitors,omeprazole(OME)and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid(DIDS),can efficiently inhibit infection of multiple herpesviruses in cellulo(i.e.,PRV,HSV and EBV),and effectively treat murine herpes simplex encephalitis(HSE).Additionally,DIDS was found to inhibit HSV-1 replication by blocking the PI3K/Akt pathway.Most importantly,both DIDS and OME were able to inhibit ACV-resistant HSV-1 strain infection.The study's findings suggest that targeting host-cell factors such as CLC-2 may be a promising approach to tackling herpesvirus drug resistance.The discovery of CLC-2 as a potential drug target for anti-herpesvirus therapy provides a new direction for the development of novel antiviral agents.
基金The authors sincerely acknowledge the financial support from the National Natural Science Foundation of China(52302343)Beijing Institute of Technology Teli Young Fellow Program(RCPT-20220029)the Beijing Institute of Technology Research Fund Program for Young Scholars(XSQD-6120220130,XSQD-202213001).
文摘The emergence of multidrug-resistant bacteria poses a significant challenge in the treatment of osteomyelitis,rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure.In recent years,triggerable biomaterial-based,antibiotic-free osteomyelitis treatment strategies have rapidly evolved,demonstrating excellent bactericidal effects.Triggerable biomaterials-based osteomyelitis theranostics encompass physical signal response strategies and host immune modulation approaches.These strategies can be effective against drug-resistant bacteria,circumventing the gradual acquisition of resistance that often accompanies traditional antibiotic treat-ment.Additionally,the inherent physical properties of the triggerable bio-materials facilitate the precise imaging of osteomyelitis.There is no doubt that triggerable biomaterial-mediated,antibiotic-free therapies are emerging as a trend,which is critically important in combating multidrug-resistant bacteria-induced osteomyelitis.In this review,we summarize the latest advances in osteomyelitis treatment strategies from both pathogen-directed and host-directed perspectives.The design regimens and specific action mechanisms of triggerable biomaterial-based nanoplatforms are also clarified.Finally,we outline the challenges faced by various antibiotic-free therapies and provide an outlook on the prospects for synergistic interactions.
