Abstract:
:Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) has emerged as an enticing new target since its function is conserved and essential for bacterial fitness, and because its inhibition or dysregulation leads to bacterial cell death. ClpP protease function controls global protein homeostasis and is, therefore, crucial for the maintenance of the bacterial proteome during growth and infection. Previously, acyldepsipeptides (ADEPs) were discovered to dysregulate ClpP, leading to bactericidal activity against both actively growing and dormant Gram-positive pathogens. Unfortunately, these compounds had very low efficacy against Gram-negative bacteria. Hence, we sought to develop non-ADEP ClpP-targeting compounds with activity against Gram-negative species and called these activators of self-compartmentalizing proteases (ACPs). These ACPs bind and dysregulate ClpP in a manner similar to ADEPs, effectively digesting bacteria from the inside out. Here, we performed further ACP derivatization and testing to improve the efficacy and breadth of coverage of selected ACPs against Gram-negative bacteria. We observed that a diverse collection of Neisseria meningitidis and Neisseria gonorrhoeae clinical isolates were exquisitely sensitive to these ACP analogues. Furthermore, based on the ACP-ClpP cocrystal structure solved here, we demonstrate that ACPs could be designed to be species specific. This validates the feasibility of drug-based targeting of ClpP in Gram-negative bacteria.
journal_name
ACS Infect Disjournal_title
ACS infectious diseasesauthors
Binepal G,Mabanglo MF,Goodreid JD,Leung E,Barghash MM,Wong KS,Lin F,Cossette M,Bansagi J,Song B,Balasco Serrão VH,Pai EF,Batey RA,Gray-Owen SD,Houry WAdoi
10.1021/acsinfecdis.0c00599subject
Has Abstractpub_date
2020-12-11 00:00:00pages
3224-3236issue
12issn
2373-8227journal_volume
6pub_type
杂志文章abstract::Stimulator of interferon genes (STING) is an integral ER-membrane protein that can be activated by 2'3'-cGAMP synthesized by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) upon binding of double-stranded DNA. It activates interferon (IFN) and inflammatory cytokine responses to defend against in...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00010
更新日期:2019-07-12 00:00:00
abstract::The envelope glycoprotein (Env) enables HIV-1 cell entry through fusion of host-cell and viral membranes induced by the transmembrane subunit gp41. Antibodies targeting the C-terminal sequence of the membrane-proximal external region (C-MPER) block the fusogenic activity of gp41 and achieve neutralization of divergent...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00243
更新日期:2020-08-14 00:00:00
abstract::The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms....
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00222
更新日期:2019-11-08 00:00:00
abstract::The general secretion (Sec) pathway is a conserved essential pathway in bacteria and is the primary route of protein export across the cytoplasmic membrane. During protein export, the signal peptidase LepB catalyzes the cleavage of the signal peptide and subsequent release of mature proteins into the extracellular spa...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.6b00075
更新日期:2016-12-09 00:00:00
abstract::To explore the possibility of constrained peptides to target Plasmodium-infected cells, we designed a J domain mimetic derived from Plasmodium falciparum calcium-dependent protein kinase 1 ( PfCDPK1) as a strategy to disrupt J domain binding and inhibit PfCDPK1 activity. The J domain disruptor (JDD) peptide was confor...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.8b00347
更新日期:2019-04-12 00:00:00
abstract::Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addition, a greater chemical space can be interrogated with structure-guided drug de...
journal_title:ACS infectious diseases
pub_type: 杂志文章,评审
doi:10.1021/acsinfecdis.7b00276
更新日期:2018-03-09 00:00:00
abstract::Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/id500028m
更新日期:2015-05-08 00:00:00
abstract::Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species o...
journal_title:ACS infectious diseases
pub_type: 杂志文章,评审
doi:10.1021/acsinfecdis.9b00019
更新日期:2019-06-14 00:00:00
abstract::Subunit vaccines composed of protein antigens covalently attached to Toll-like receptor (TLR) agonists elicit superior immune responses compared to mixtures of antigens and TLR agonists. Among different conjugation approaches, enzyme-mediated ligation is one of the few that provides an opportunity for the generation o...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00047
更新日期:2020-07-10 00:00:00
abstract::Vaccines and antivirals to combat dengue, Zika, and other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses and the propensity of non-neutralizing, cross-reactive antibodies to facilitate cellular infection and increas...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.8b00322
更新日期:2019-03-08 00:00:00
abstract::Negamycin is a hydrophilic antimicrobial translation inhibitor that crosses the lipophilic inner membrane of Escherichia coli via at least two transport routes to reach its intracellular target. In a minimal salts medium, negamycin's peptidic nature allows illicit entry via a high-affinity route by hijacking the Dpp d...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.5b00027
更新日期:2015-05-08 00:00:00
abstract::Dysentery is a major health threat that dramatically impacts childhood morbidity and mortality in developing countries. Various pathogenic agents cause dysentery, such as Shigella spp. and Escherichia coli, which are very closely related if not identical species. Sensitive and precise detection and identification of t...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00199
更新日期:2019-11-08 00:00:00
abstract::Brain-eating amoebae cause devastating infections in the central nervous system of humans, resulting in a mortality rate of 95%. There are limited effective therapeutic options available clinically for treating granulomatous amoebic encephalitis and primary amoebic meningoencephalitis caused by Acanthamoeba castellani...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00263
更新日期:2019-12-13 00:00:00
abstract::Viridicatumtoxins are a rare class of tetracycline-like antibiotics that strongly inhibit drug-resistant Gram-positive bacteria. Although reported to exhibit in vitro inhibition activity to undecaprenyl pyrophosphate synthase (UPPS), an essential enzyme in bacterial cell wall synthesis, the biological targets and mech...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00031
更新日期:2020-07-10 00:00:00
abstract::RNA-dependent RNA polymerases (RdRPs) from nonsegmented negative strand (NNS) RNA viruses perform both mRNA transcription and genome replication, and these activities are regulated by their interactions with RNA and other accessory proteins within the ribonucleoprotein (RNP) complex. Detailed biochemical characterizat...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00554
更新日期:2020-10-09 00:00:00
abstract::Intravenous artesunate is effective against cerebral malaria (CM), but high mortality and neurological sequelae in survivors are inevitable. We investigated the effect of combined artesunate and tetramethylpyrazine using mouse models of experimental cerebral malaria (ECM). Artesunate + tetramethylpyrazine reduced micr...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00124
更新日期:2020-09-11 00:00:00
abstract::Candida albicans is an opportunistic pathogenic yeast and is responsible for candidiasis. It readily colonizes host tissues and implant devices, and forms biofilms, which play an important role in pathogenesis and drug resistance. In this study, the antibiofilm, antihyphal, and antivirulence activities of nepodin, iso...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00033
更新日期:2019-07-12 00:00:00
abstract::The ability to respire and generate adenosine triphosphate (ATP) is essential for the physiology, persistence, and pathogenicity of Mycobacterium tuberculosis, which causes tuberculosis. By employing a lead repurposing strategy, the malarial cytochrome bc1 inhibitor SCR0911 was tested against mycobacteria. Docking stu...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00408
更新日期:2020-04-10 00:00:00
abstract::The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-...
journal_title:ACS infectious diseases
pub_type: 杂志文章,评审
doi:10.1021/acsinfecdis.0c00052
更新日期:2020-05-08 00:00:00
abstract::MmpL3, an essential mycolate transporter in the inner membrane of Mycobacterium tuberculosis (Mtb), has been identified as a target of multiple, chemically diverse antitubercular drugs. However, several of these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we ...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00675
更新日期:2021-01-08 00:00:00
abstract::A method for the fast isolation, propagation, and characterization of very low count bacteriophages active against pathogenic bacterial strains is described in this study. Bacteriophages with a count of 102 phage particles were dynamically adhered from the maximum 10 mL blood plasma sample onto the nanostructured part...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.0c00358
更新日期:2020-10-09 00:00:00
abstract::Multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis are resistant to first- and second-line drug regimens and resulted in 210,000 fatalities in 2013. In the current study, we screened a library of aquatic bacterial natural product fractions for their ability to inhibit this pathogen. A frac...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.5b00005
更新日期:2015-04-10 00:00:00
abstract::Pandemics such as influenza, smallpox, and plague have caused the loss of hundreds of millions of lives and have occurred for many centuries. Fortunately, they have been largely eliminated by the use of vaccinations and drugs. More recently, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (M...
journal_title:ACS infectious diseases
pub_type: 历史文章,杂志文章,评审
doi:10.1021/acsinfecdis.0c00291
更新日期:2020-07-10 00:00:00
abstract::Violacein is a tryptophan-derived purple pigment produced by environmental bacteria, which displays multiple biological activities, including strong inhibition of Gram-positive pathogens. Here, we applied a combination of experimental approaches to identify the mechanism by which violacein kills Gram-positive bacteria...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.8b00245
更新日期:2019-04-12 00:00:00
abstract::Malaria continues to be a significant cause of death and morbidity worldwide, and there is a need for new antimalarial drugs with novel targets. We have focused as a potential target for drug development on N-myristoyl transferase (NMT), an enzyme that acylates a wide range of substrate proteins. The NMT substrates in...
journal_title:ACS infectious diseases
pub_type: 杂志文章,评审
doi:10.1021/acsinfecdis.7b00203
更新日期:2018-04-13 00:00:00
abstract::The α-Gal antigen [Galα(1,3)Galβ(1,4)GlcNAcα] is an immunodominant epitope displayed by infective trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. A virus-like particle displaying a high density of α-Gal was found to be a superior reagent for the ELISA-based serological diagnosis of Ch...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.6b00114
更新日期:2016-12-09 00:00:00
abstract::The genomes of diverse mycobacterial species encode multiple proteins with the canonical l,d-transpeptidase (Ldt) sequence motif. The reason for this apparent redundancy is not well understood, but evidence suggests paralogous Ldts may serve niche roles in maintaining and/or remodeling mycobacterial peptidoglycan. We ...
journal_title:ACS infectious diseases
pub_type: 信件
doi:10.1021/acsinfecdis.9b00234
更新日期:2019-12-13 00:00:00
abstract::The Burkholderia cepacia complex is a group of Gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). Burkholderia are intrinsically resistant to many antibiotics and the lack of antibiotic development ne...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.7b00235
更新日期:2018-05-11 00:00:00
abstract::4-Oxo-4-phenyl-but-2-enoates inhibit MenB, the 1,4-dihydroxyl-2-naphthoyl-CoA synthase in the bacterial menaquinone (MK) biosynthesis pathway, through the formation of an adduct with coenzyme A (CoA). Here, we show that the corresponding methyl butenoates have MIC values as low as 0.35-0.75 µg/mL against drug sensitiv...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.6b00023
更新日期:2016-05-13 00:00:00
abstract::Although iron is essential for bacteria, the nutrient presents problems of toxicity and solubility. Bacteria circumvent these problems with the aid of iron storage proteins where Fe3+ is deposited and, when necessary, mobilized as Fe2+ for metabolic requirements. In Pseudomonas aeruginosa, Fe3+ is compartmentalized in...
journal_title:ACS infectious diseases
pub_type: 杂志文章
doi:10.1021/acsinfecdis.9b00398
更新日期:2020-03-13 00:00:00