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Review
. 2022 Apr;4(1):FDD73.
doi: 10.4155/fdd-2022-0001. Epub 2022 May 5.

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

Colin J Suckling  1 , Iain S Hunter  2 , Fraser J Scott  1
Affiliations
Review

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

Colin J Suckling et al. Future Drug Discov. 2022 Apr.

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.

Keywords: DNA; RNA; Strathclyde minor groove binders; anti-infectives; antimicrobial resistance; multitargeting anti-infective drugs; nucleic acids; strathclyde nucleic acid binders.

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Conflict of interest statement

Financial & competing interests disclosure This work was supported in part by grants from: UKRI: The differing biological fates of DNA minor groove-binding (MGB) antibiotics in Gram-negative and Gram-positive bacteria BBSRCBB/N007999/12014–2017. The differing biological fates of DNA MGBs MRC Confidence in Concept 2013–2014. A new drug discovery pipeline for animal African trypanosomiasis BBSRCBB/N007638/12015–2019. The work was supported by the Wellcome Trust: Tackling MDR Gram-negative infections by an MGB conjugation strategy 210103/Z/18/Z. The work was supported by the Chief Scientist's Office: Investigating A Novel Class Of Gram-Negative Active Antibiotic Suitable For Clinical Use TCS/19/33. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Single-targeted and multitargeted anti-infective drugs.
Figure 2.
Figure 2.. The structures of the natural products distamycin and netropsin.
Figure 3.
Figure 3.. Exemplar structural modifications to the distamycin template that are seen in Strathclyde minor groove binders.
Figure 4.
Figure 4.. Structures of antibacterial Strathclyde minor groove binders.
Figure 5.
Figure 5.. Structure of MGB-BP-3.
Figure 6.
Figure 6.. Structure of antimycobacterial Strathclyde minor groove binders.
Figure 7.
Figure 7.. Structure of antimalarial Strathclyde minor groove binders.
Figure 8.
Figure 8.. Structures and activities of antiparasitic Strathclyde minor groove binders.
Tc: Trypanosoma congolense IC50; Tv: Trypanosoma vivax IC50; SI: Selectivity index, defined as HEK293T cell IC50 divided by Tc or Tv IC50.
Figure 9.
Figure 9.. Structure of antifungal Strathclyde minor groove binders.
Figure 10.
Figure 10.. Structures of antiviral Strathclyde minor groove binders.
See this image and copyright information in PMC

References

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