A Structural View on Medicinal Chemistry Strategies against Drug Resistance

Abstract

The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future.

Fast Cyclization of a Proline‐Derived Self‐Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

“…This observation indicates that fast SI spacers are fundamental to quickly reach high concentrations of active compound in the tumor microenvironment, which may prevent the development of drug resistance and the proliferation of resilient cells. [28] These in vitro data hold promise for the installation of the Sp4 spacer in alarge subset of platforms that can be activated for in vivo therapy and diagnosis.The rate of self-immolative cleavage is expected to be particularly relevant in the context of non-internalizing conjugates. [25] In fact, in this case the therapeutic outcome is ac omposite result of efficient targeting, rate of linker cleavage (SI spacer activation), and rate of SI spacer degradation, which may regulate the competition between drug entry into the cells and drug escape back into the bloodstream.…”

Combatting the evolution of antifungal resistance in Cryptococcus neoformans

“…In Saccharomyces cerevisiae, lanosterol 14α‐demethylase, bearing a tyrosine 145 mutation in the catalytic domain, induces a disruption to a water‐mediated hydrogen bond network that consists of a tertiary hydroxyl absent in long‐tailed azoles, such as itraconazole and posaconazole (Sagatova et al ., 2016). Consequently, a disruption in the hydrogen bonding network results in decreased binding affinity and reduced susceptibility to short‐tailed azoles (Agnello et al ., 2019).…”

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

“…cefiderocol 4,5 and BAL30072 6 that both have a siderophore attached to a known scaffold). Another approach is to fight these resistances, by developing small molecules that, in combination with an antibiotic can preserve or restore its activity, 7 in particular by inhibiting β-lactamases (BLs). 8 While most research had been restricted to β-lactam-based inhibitor, such as clavulanic acid, non-β-lactam-based inhibitors are now actively studied ( Figure 1B).…”