Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Fernández‐Villa, Daniel; Aguilar, María Rosa; Rojo, Luís

doi:10.3390/ijms20204996

Cited by 128 publications

(93 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4). The most potent of the 28 compounds was an antibacterial diaminopyridine propargyl-linked antifolate 15 , MMV1580844 (IC 50 = 0.0017 μM), which targets DHFR in mammalian and yeast cells 16,17 , and was active against P. berghei liver stages (0.004 μM) but not PfNF54 stage IV/V gametocytes, supporting previous reports that inhibition of Plasmodium DHFR is effective in asexual and liver stages 6 . MMV1580844 had a pronounced (63-fold) loss of activity against pyrimethamineresistant PfDd2.…”

Section: Resultssupporting

confidence: 78%

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

et al. 2021

View full text Add to dashboard Cite

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.

show abstract

Section: Resultssupporting

confidence: 78%

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The anti-rsPilA NRel adaptive amino acid transport & metabolism state provided insight into the mechanism of this population’s uniquely increased susceptibility to TMP-SMX, because the sulfonamide class of antibiotic targets the folic acid synthesis pathway involved in amino acid synthesis [ 95 ]. Also, compared to anti- IHF NRel, the lower relative expression of folA and folP, which encode the protein targets for TMP and SMX, respectively, together with lower expression of emrA and emrB , which encode subunits of the EmrAB efflux pump that transports TMP-SMX out of the cell, also supported the greater sensitivity to TMP-SMX of anti-rsPilA vs. anti- IHF NRels.…”

Section: Discussionmentioning

confidence: 99%

Nontypeable Haemophilus influenzae newly released (NRel) from biofilms by antibody-mediated dispersal versus antibody-mediated disruption are phenotypically distinct

Mokrzan

Ahearn

Buzzo

et al. 2020

Biofilm

View full text Add to dashboard Cite

“…One example of such molecules is antifolates, with folic acid as the central molecule of their metabolism [ 49 ]. Folic acid or folate is a group of water-soluble metabolites that belong to the B-vitamin family, namely B 9 .…”

Section: Microbial Targeting Strategiesmentioning

confidence: 99%

Polymeric Nanoparticles for Antimicrobial Therapies: An up-to-date Overview

et al. 2021

View full text Add to dashboard Cite

Despite the many advancements in the pharmaceutical and medical fields and the development of numerous antimicrobial drugs aimed to suppress and destroy pathogenic microorganisms, infectious diseases still represent a major health threat affecting millions of lives daily. In addition to the limitations of antimicrobial drugs associated with low transportation rate, water solubility, oral bioavailability and stability, inefficient drug targeting, considerable toxicity, and limited patient compliance, the major cause for their inefficiency is the antimicrobial resistance of microorganisms. In this context, the risk of a pre-antibiotic era is a real possibility. For this reason, the research focus has shifted toward the discovery and development of novel and alternative antimicrobial agents that could overcome the challenges associated with conventional drugs. Nanotechnology is a possible alternative, as there is significant evidence of the broad-spectrum antimicrobial activity of nanomaterials and nanoparticles in particular. Moreover, owing to their considerable advantages regarding their efficient cargo dissolving, entrapment, encapsulation, or surface attachment, the possibility of forming antimicrobial groups for specific targeting and destruction, biocompatibility and biodegradability, low toxicity, and synergistic therapy, polymeric nanoparticles have received considerable attention as potential antimicrobial drug delivery agents. In this context, the aim of this paper is to provide an up-to-date overview of the most recent studies investigating polymeric nanoparticles designed for antimicrobial therapies, describing both their targeting strategies and their effects.

show abstract

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Cited by 128 publications

References 114 publications

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box

Nontypeable Haemophilus influenzae newly released (NRel) from biofilms by antibody-mediated dispersal versus antibody-mediated disruption are phenotypically distinct

Polymeric Nanoparticles for Antimicrobial Therapies: An up-to-date Overview

Contact Info

Product

Resources

About