From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials

Abstract

Macrolides, as a class of natural or semisynthetic products, express their antibacterial activity primarily by reversible binding to the bacterial 50S ribosomal subunits and by blocking nascent proteins’ progression through their exit tunnel in bacterial protein biosynthesis. Generally considered to be bacteriostatic, they may also be bactericidal at higher doses. The discovery of azithromycin from the class of macrolides, as one of the most important new drugs of the 20th century, is presented as an example of a rational medicinal chemistry approach to drug design, applying classical structure-activity relationship that will illustrate an impressive drug discovery success story. However, the microorganisms have developed several mechanisms to acquire resistance to antibiotics, including macrolide antibiotics. The primary mechanism for acquiring bacterial resistance to macrolides is a mutation of one or more nucleotides from the binding site. Although azithromycin is reported to show different, two-step process of the inhibition of ribosome function of some species, more detailed elaboration of that specific mode of action is needed. New macrocyclic derivatives, which could be more potent and less prone to escape bacterial resistance mechanisms, are also continuously evaluated. A novel class of antibiotic compounds—macrolones, which are derived from macrolides and comprise macrocyclic moiety, linker, and either free or esterified quinolone 3-carboxylic group, show excellent antibacterial potency towards key erythromycin-resistant Gram-positive and Gram-negative bacterial strains, with possibly decreased potential of bacterial resistance to macrolides.

Azithromycin Inhibits the Replication of Zika Virus

“…In our study we investigated the in vitro efficacy against ZIKV of AZ (new semisynthetic 15-membered ring azalide antibiotic belonging to the subclass of macrolides) [34] in a cell culture model because preliminary data suggested the efficacy of a singledose of AZ reduced the proliferation of ZIKV in glial cells [7]. AZ is a safe molecule during pregnancy [13,35,36].…”

“…The main mechanism of action of AZ on bacteria is through binding with the 50s ribosomal subunit and inhibition of messenger RNAdirected polypeptide synthesis [34]. Hypotheses on the mechanism of action of macrolides on viruses are scarce.…”

“…Macrolides are bacteriostatic agents that prevent the growth of bacteria while not killing them [34]. The inhibition of ZIKV replication after a single dose of AZ mimics a bacteriostatic curve.…”

Dissecting the collateral damage of antibiotics on gut microbes

“…We thus wondered at which level macrolides and tetracyclines exert a differential effect on gut microbes. Although traditionally both clinical use 34-37 and basic research 38,39 heavily rely on this distinction between bactericidal and bacteriostatic antibiotics, there are reports of drugs changing their killing capacity depending on the organism, drug concentration or medium tested 40,41 (and increased evidence from meta-analyses that the distinction may have little relevance to clinical practice 42,43 ). We therefore hypothesized that this bacteriostatic/bactericidal divide may be less rigid for gut commensals, which are more phylogenetically diverse than the few pathogens usually tested, and hence provide a level where the effect of these drug classes on gut microbes becomes differential.…”

An <em>In Silico</em> Study of a Novel rpoB Insertion in a Cluster of Clinical Strains of <em>Mycobacterium tuberculosis</em> Highly-Rifampicin Resistant

“…Tables 1 and 2 show the results of the screening for potential inhibitors of wtRNAP and mRNAP respectively. With the exception of remikiren (Clozel and Fischli, 1993), a renin inhibitor in development for the treatment of hypertension, the other compounds, anidulafungin (Denning, 2002), capreomycin (Johansen et al, 2006) and erythromycin (Jelić and Antolović, 2016), have antibiotic activity, although the targets involved in the pharmacological action are other than RNAP. (Jelić and Antolović, 2016) b (Johansen et al, 2006) c (Clozel and Fischli, 1993) d (Denning, 2002) e (Yarbrough et al, 1976) …”