Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design

Abstract

Genetic information is translated into proteins by the ribosome. Structural studies of the ribosome and of its complexes with factors and inhibitors have provided invaluable information on the mechanism of protein synthesis. Ribosome inhibitors are among the most successful antimicrobial drugs and constitute more than half of all medicines used to treat infections. However, bacterial infections are becoming increasingly difficult to treat because the microbes have developed resistance to the most effective antibiotics, creating a major public health care threat. This has spurred a renewed interest in structure-function studies of protein synthesis inhibitors, and in few cases, compounds have been developed into potent therapeutic agents against drug-resistant pathogens. In this review, we describe the modes of action of many ribosome-targeting antibiotics, highlight the major resistance mechanisms developed by pathogenic bacteria, and discuss recent advances in structure-assisted design of new molecules.

Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule

“…Most compounds that target the ribosome affect a large number of mRNAs through general inhibition of translation initiation or elongation [1][2][3] . Furthermore, these compounds almost exclusively act as broad-spectrum inhibitors, displaying little sequence specificity 4 .…”

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

“…These drugs were intraperitoneally injected into C57BL/6J mice at time of infection with an E. coli strain carrying resistance to tetracyclines (TetR) and chloramphenicol (CamR) to control for the effects of ribosomal-targeting antibiotics directly on bacterial viability. From the panel of tested drugs, treatment with low-dose doxycycline, a tetracycline antibiotic known to bind to the mitochondrial ribosome and block translation of mitochondrial-encoded mRNA (Lin et al, 2018), revealed a robust and reproducible increase in survival in multiple independent experiments ( Figure 1A). We used rectal temperature and body weight measurements to assess disease severity and found that doxycycline-treated mice had less severe hypothermia than PBS-treated controls and increased body temperature close to normal levels within 48h of infection ( Figure 1B).…”

“…Having documented a direct host-dependent effect of doxycycline leading to disease tolerance against sepsis, we then explored the hypothesis that doxycycline protection is initiated and dependent on mitochondrial function perturbations. We first explored the possibility that doxycycline treatment could increase the availability of the elongation factor Tu (TUFM) as this antibiotic works by blocking the binding of aminoacyl-tRNA (aa-tRNA) to the A site of the ribosome, decreasing the use of TUFM which is part of the ternary complex (aa-tRNA, TUFM and GTP) that decodes the gene open reading frame (Lin et al, 2018). If this would be the case, increased availability of TUFM could play a role in disease tolerance because TUFM has been shown to interact with NLRX1 causing reduction of type I interferon and enhancement of autophagy (Lei et al, 2013).…”

Deletion of RsmE 16S rRNA methyltransferase leads to low level increase in aminoglycoside resistance inMycobacterium smegmatis

“…The decoding centre of ribosome ensures error-free selection of cognate tRNA to mRNA, promoting translation accuracy (Ogle et al, 2003;Mahto and Chow 2013). Antibiotics of several classes, target the decoding centre by binding around helix 44 and inhibiting protein translation (Wilson 2014;Lin et al, 2018).…”