Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Multitargeted anti-infective drugs: resilience to resistance in the antimicrobial resistance era.

ABSTRACT: The standard drug discovery paradigm of single molecule - single biological target - single biological effect is perhaps particularly unsuitable for anti-infective drug discovery. This is due to the rapid evolution of resistance likely to be observed with single target drugs. Multitargeted anti-infective drugs are likely to be superior due to their lower susceptibility to target-related resistance mechanisms. Strathclyde minor groove binders are a class of compounds which have been developed by adopting the multitargeted anti-infective drugs paradigm, and their effectiveness against a wide range of pathogenic organisms is discussed. The renaming of this class to Strathclyde nucleic acid binders is also presented due to their likely targets including both DNA and RNA.

SUBMITTER: Suckling CJ

PROVIDER: S-EPMC9112235 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Multitargeted anti-infective drugs: resilience to resistance in the antimicrobial resistance era.

Suckling Colin J CJ Hunter Iain S IS Scott Fraser J FJ

Future drug discovery 20220401 1

The standard drug discovery paradigm of single molecule - single biological target - single biological effect is perhaps particularly unsuitable for anti-infective drug discovery. This is due to the rapid evolution of resistance likely to be observed with single target drugs. Multitargeted anti-infective drugs are likely to be superior due to their lower susceptibility to target-related resistance mechanisms. Strathclyde minor groove binders are a class of compounds which have been developed by ...[more]

PMID: 35600289

Similar Datasets

Antimicrobial Peptides as Anti-Infective Agents in Pre-Post-Antibiotic Era?

Project description:Resistance to antibiotics is one of the main current threats to human health and every year multi-drug resistant bacteria are infecting millions of people worldwide, with many dying as a result. Ever since their discovery, some 40 years ago, the antimicrobial peptides (AMPs) of innate defense have been hailed as a potential alternative to conventional antibiotics due to their relatively low potential to elicit resistance. Despite continued effort by both academia and start-ups, currently there are still no antibiotics based on AMPs in use. In this study, we discuss what we know and what we do not know about these agents, and what we need to know to successfully translate discovery to application. Understanding the complex mechanics of action of these peptides is the main prerequisite for identifying and/or designing or redesigning novel molecules with potent biological activity. However, other aspects also need to be well elucidated, i.e., the (bio)synthetic processes, physiological and pathological contexts of their activity, and a quantitative understanding of how physico-chemical properties affect activity. Research groups worldwide are using biological, biophysical, and algorithmic techniques to develop models aimed at designing molecules with the necessary blend of antimicrobial potency and low toxicity. Shedding light on some open questions may contribute toward improving this process.

| S-EPMC6887943 | biostudies-literature

Antimicrobial Resistance in the COVID-19 Landscape: Is There an Opportunity for Anti-Infective Antibodies and Antimicrobial Peptides?

Project description:Although COVID-19 has captured most of the public health attention, antimicrobial resistance (AMR) has not disappeared. To prevent the escape of resistant microorganisms in animals or environmental reservoirs a "one health approach" is desirable. In this context of COVID-19, AMR has probably been affected by the inappropriate or over-use of antibiotics. The increased use of antimicrobials and biocides for disinfection may have enhanced the prevalence of AMR. Antibiotics have been used empirically in patients with COVID-19 to avoid or prevent bacterial coinfection or superinfections. On the other hand, the measures to prevent the transmission of COVID-19 could have reduced the risk of the emergence of multidrug-resistant microorganisms. Since we do not currently have a sterilizing vaccine against SARS-CoV-2, the virus may still multiply in the organism and new mutations may occur. As a consequence, there is a risk of the appearance of new variants. Nature-derived anti-infective agents, such as antibodies and antimicrobial peptides (AMPs), are very promising in the fight against infectious diseases, because they are less likely to develop resistance, even though further investigation is still required.

| S-EPMC9205220 | biostudies-literature

Antimicrobial Drugs in Fighting against Antimicrobial Resistance.

Project description:The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants), the community level resistance (i.e., bilofilms and persisters) is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals.

| S-EPMC4824775 | biostudies-literature

Catastrophic Perforation in Streptococcus Pneumoniae Aortitis: Complications of Infective Endocarditis in the Current Antimicrobial Era.

Project description:Infectious aortitis is an uncommon but life-threatening cause of aortitis. Given the lack of specific symptoms, establishing the diagnosis is often a challenge. When it is associated with an endovascular infection, such as infective endocarditis, blood cultures may be diagnostic although often limited by low positive predictive value. Imaging studies may reveal characteristic findings, with computerized tomography angiography being the most sensitive. Management includes prompt initiation of antimicrobial therapy followed by surgical intervention, keeping in mind that operative mortality is high due to weakened arterial wall integrity. Here we describe a 25-year-old woman without relevant medical history, who presented to the hospital with subacute onset of fever, back pain and malaise, and was found to have infectious aortitis secondary to Streptococcus pneumoniae endocarditis. Despite appropriate antimicrobial coverage and surgical repair attempts, she succumbed to aortic perforation after a complicated and prolonged hospitalization.

| S-EPMC9195106 | biostudies-literature

Antimicrobial Spectrum of Titroleane™: A New Potent Anti-Infective Agent.

Project description:Tea Tree oil (TTO) is well known for its numerous good properties but might be also irritating or toxic when used topically or ingested, thus limiting the number of possible applications in Humans. The aim of the study was to characterize the antimicrobial spectrum as well as the toxicity of Titroleane™, a new anti-infective agent obtained from TTO but cleared of its toxic monoterpenes part. The susceptibility to Titroleane™ of various pathogens (bacteria and fungi) encountered in animal and human health was studied in comparison with that of TTO. Antimicrobial screening was carried out using the broth microdilution method. Activities against aerobic, anaerobic, fastidious and non-fastidious microorganisms were performed. For all microorganisms tested, the MIC values for Titroleane™ ranged from 0.08% to 2.5%, except for Campylobacter jejuni, and Aspergillus niger. In particular, Titroleane™ showed good efficacy against skin and soft tissue infection pathogens, such as methicillin resistant Staphylococcus aureus (MRSA), intra-abdominal infections and oral pathogens, as well as fish farming pathogens. Toxicity testing showed little and similar cytotoxicities between TTO and Titroleane™ of 37% and 23%, respectively at a concentration of 0.025% (v/v). Finally, we demonstrated that the antimicrobial activity of Titroleane™ is similar to that of TTO.

| S-EPMC7400619 | biostudies-literature

An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities.

Project description:Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.

| S-EPMC5090204 | biostudies-literature

Epigenetic polypharmacology: from combination therapy to multitargeted drugs.

Project description:The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.

| S-EPMC5062873 | biostudies-literature

Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents.

Project description:Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-? using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-?B activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-? and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.

| S-EPMC7443334 | biostudies-literature

Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance.

Project description:Given the increase in resistance to antibacterial agents, there is an urgent need for the development of new agents with novel modes of action. As an interim solution, it is also prudent to reinvestigate old or abandoned antibacterial compounds to assess their efficacy in the context of widespread resistance to conventional agents. In the 1970s, much work was performed on the development of peptide mimetics, exemplified by the phosphonopeptide, alafosfalin. We investigated the activity of alafosfalin, di-alanyl fosfalin and β-chloro-L-alanyl-β-chloro-L-alanine against 297 bacterial isolates, including carbapenemase-producing Enterobacterales (CPE) (n = 128), methicillin-resistant Staphylococcus aureus (MRSA) (n = 37) and glycopeptide-resistant enterococci (GRE) (n = 43). The interaction of alafosfalin with meropenem was also examined against 20 isolates of CPE. The MIC50 and MIC90 of alafosfalin for CPE were 1 mg/L and 4 mg/L, respectively and alafosfalin acted synergistically when combined with meropenem against 16 of 20 isolates of CPE. Di-alanyl fosfalin showed potent activity against glycopeptide-resistant isolates of Enterococcus faecalis (MIC90; 0.5 mg/L) and Enterococcus faecium (MIC90; 2 mg/L). Alafosfalin was only moderately active against MRSA (MIC90; 8 mg/L), whereas β-chloro-L-alanyl-β-chloro-L-alanine was slightly more active (MIC90; 4 mg/L). This study shows that phosphonopeptides, including alafosfalin, may have a therapeutic role to play in an era of increasing antibacterial resistance.

| S-EPMC7144462 | biostudies-literature

NLRP3 inflammasome is a target for development of broad-spectrum anti-infective drugs.

Project description:We describe the molecular mode of action and pharmacodynamics of a new molecular entity (NME) that induces the NLRP3 inflammasome-mediated innate immune response. This innate response reduces the pathogen load in an experimentally induced methicillin-resistant Staphylococcos aureus infection, enhances survival in an experimentally induced Gram-negative bacteremia, and overrides the escape mechanism of an obligate intracellular pathogen, viz. Chlamydia pneumoniae. Furthermore, the NME is more effective than standard-of-care antibiotic therapy in a clinically established multifactorial bacterial infection. Analysis of transcriptional regulation of inflammasome signaling genes and innate/adaptive immune genes revealed consistent and significant host changes responsible for the improved outcomes in these infections. These studies pave the way for the development of first-in-class drugs that enhance inflammasome-mediated pathogen clearance and identify the NLRP3 inflammasome as a drug target to address the global problem of emerging new infectious diseases and the reemergence of old diseases in an antibiotic-resistant form.

| S-EPMC3318317 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data