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

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.

[1]  Frederick R. C. Simeons,et al.  Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis , 2022, Journal of medicinal chemistry.

[2]  K. Parang,et al.  Small Amphiphilic Peptides: Activity Against a Broad Range of Drug-Resistant Bacteria and Structural Insight into Membranolytic Properties. , 2022, Journal of medicinal chemistry.

[3]  OUP accepted manuscript , 2022, Journal of Antimicrobial Chemotherapy.

[4]  S. Li,et al.  Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist. , 2021, Journal of medicinal chemistry.

[5]  D. Hochhauser,et al.  Effects of N-terminus modified Hx-amides on DNA binding affinity, sequence specificity, cellular uptake, and gene expression. , 2021, Bioorganic & medicinal chemistry letters.

[6]  D. Shlaes.  Innovation, Nontraditional Antibacterial Drugs, and Clinical Utility. , 2021, ACS infectious diseases.

[7]  Sarah L. Williams,et al.  Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria. , 2021, Journal of medicinal chemistry.

[8]  Peng Sang,et al.  Modular Design of Membrane-Active Antibiotics: From Macromolecular Antimicrobials to Small Scorpionlike Peptidomimetics. , 2021, Journal of medicinal chemistry.

[9]  G. Lau,et al.  Random Peptide Mixtures as Safe and Effective Antimicrobials against Pseudomonas aeruginosa and MRSA in Mouse Models of Bacteremia and Pneumonia. , 2021, ACS infectious diseases.

[10]  C. Schiffer,et al.  Inhibiting HTLV-1 Protease: A Viable Antiviral Target. , 2021, ACS chemical biology.

[11]  A. Ebata,et al.  To Push or To Pull? In a Post-COVID World, Supporting and Incentivizing Antimicrobial Drug Development Must Become a Governmental Priority , 2021, ACS infectious diseases.

[12]  N. Tucker,et al.  Novel antibiotic mode of action by repression of promoter isomerisation , 2021, bioRxiv.

[13]  C. Suckling,et al.  The potential for new and resilient anti-cancer drugs based upon minor groove binders for DNA , 2021, Medical Research Archives.

[14]  C. Sheng,et al.  Discovery of Novel Fungal Lanosterol 14α-Demethylase (CYP51)/Histone Deacetylase (HDAC) Dual Inhibitors to Treat Azole-resistant Candidiasis. , 2020, Journal of medicinal chemistry.

[15]  Michaela Wenzel,et al.  Multitarget Approaches against Multiresistant Superbugs , 2020, ACS infectious diseases.

[16]  Charles B. Hodges.  January 2020 , 2019, Current History.

[17]  Fraser J. Scott,et al.  Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model. , 2019, Journal of medicinal chemistry.

[18]  I. Rozas,et al.  Recent developments in compounds acting in the DNA minor groove. , 2019, MedChemComm.

[19]  J. Hartley,et al.  Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine , 2018, Scientific Reports.

[20]  D. Arya,et al.  An overview of recent advances in duplex DNA recognition by small molecules , 2018, Beilstein journal of organic chemistry.

[21]  Fraser J. Scott,et al.  Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial agents and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy , 2017, The Journal of antimicrobial chemotherapy.

[22]  M. Barrett,et al.  An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics. , 2017, European journal of medicinal chemistry.

[23]  W. Sippl,et al.  Synthesis, biological characterisation and structure activity relationships of aromatic bisamidines active against Plasmodium falciparum. , 2017, European journal of medicinal chemistry.

[24]  V. Avery,et al.  Selective anti-malarial minor groove binders. , 2016, Bioorganic & medicinal chemistry letters.

[25]  M. Cooper.  A community-based approach to new antibiotic discovery , 2015, Nature Reviews Drug Discovery.

[26]  M. Barrett,et al.  Minor groove binders as anti-infective agents. , 2013, Pharmacology & therapeutics.

[27]  Supa Hannongbua,et al.  A detailed binding free energy study of 2:1 ligand-DNA complex formation by experiment and simulation. , 2009, Physical chemistry chemical physics : PCCP.

[28]  G. S. Kumar,et al.  RNA targeting by DNA binding drugs: structural, conformational and energetic aspects of the binding of quinacrine and DAPI to A-form and H(L)-form of poly(rC).poly(rG). , 2007, Biochimica et biophysica acta.

[29]  Jean-Jacques Helesbeux,et al.  Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups. , 2007, Journal of medicinal chemistry.

[30]  S. Mackay,et al.  Short lexitropsin that recognizes the DNA minor groove at 5'-ACTAGT-3': understanding the role of isopropyl-thiazole. , 2004, Journal of the American Chemical Society.

[31]  Kirk W. Johnson,et al.  DNA binding ligands with in vivo efficacy in murine models of bacterial infection: optimization of internal aromatic amino acids. , 2004, Bioorganic & medicinal chemistry letters.

[32]  S. Mackay,et al.  DNA binding of a short lexitropsin. , 2004, Bioorganic & medicinal chemistry letters.

[33]  Tom Brown,et al.  DNA sequence recognition by an isopropyl substituted thiazole polyamide. , 2004, Nucleic acids research.

[34]  M. Sundaralingam,et al.  Structure of the side-by-side binding of distamycin to d(GTATATAC)2. , 1999, Acta crystallographica. Section D, Biological crystallography.

[35]  A. Rich,et al.  Molecular structure of the A-tract DNA dodecamer d(CGCAAATTTGCG) complexed with the minor groove binding drug netropsin. , 1993, Biochemistry.

[36]  J. Veal,et al.  DAPI (4',6-diamidino-2-phenylindole) binds differently to DNA and RNA: minor-groove binding at AT sites and intercalation at AU sites. , 1992, Biochemistry.