The macrolide antibiotic renaissance

Abstract

Macrolides represent a large family of protein synthesis inhibitors of great clinical interest due to their applicability to human medicine. Macrolides are composed of a macrocyclic lactone of different ring sizes, to which one or more deoxy-sugar or amino sugar residues are attached. Macrolides act as antibiotics by binding to bacterial 50S ribosomal subunit and interfering with protein synthesis. The high affinity of macrolides for bacterial ribosomes, together with the highly conserved structure of ribosomes across virtually all of the bacterial species, is consistent with their broad-spectrum activity. Since the discovery of the progenitor macrolide, erythromycin, in 1950, many derivatives have been synthesised, leading to compounds with better bioavailability and acid stability and improved pharmacokinetics. These efforts led to the second generation of macrolides, including well-known members such as azithromycin and clarithromycin. Subsequently, in order to address increasing antibiotic resistance, a third generation of macrolides displaying improved activity against many macrolide resistant strains was developed. However, these improvements were accompanied with serious side effects, leading to disappointment and causing many researchers to stop working on macrolide derivatives, assuming that this procedure had reached the end. In contrast, a recent published breakthrough introduced a new chemical platform for synthesis and discovery of a wide range of diverse macrolide antibiotics. This chemical synthesis revolution, in combination with reduction in the side effects, namely, 'Ketek effects', has led to a macrolide renaissance, increasing the hope for novel and safe therapeutic agents to combat serious human infectious diseases.

Application of Antibiotics/Antimicrobial Agents on Dental Caries

“…Macrolides, a polyketide class of natural products that consist of a large macrocyclic lactone ring, are typically used to treat infections caused by β-haemolytic streptococci, pneumococci, staphylococci, and enterococci, having a slightly wider antimicrobial spectrum than penicillin [53,54]. Macrolides prevent peptidyl transferase from adding the growing peptide attached to tRNA to the next amino acid and can inhibit ribosomal translation by reversibly binding to the P site on the 50S subunit of the bacterial ribosome [55].…”

LSTrAP-Crowd: Prediction of novel components of bacterial ribosomes with crowd-sourced analysis of RNA sequencing data

“…Bacteria can be intrinsically less sensitive to antibiotics due to less efficient uptake of antibiotics or mutations in ribosomal proteins that result in decreased drug□binding efficiency (Wilson, 2014; Dinos, 2017). The most frequently encountered acquired resistance mechanism involves the methylation of the ribosomal RNA (e.g., by Erm family methyltransferases), which results in decreased drug□binding efficiency and increased viability in the presence of antibiotics (Wilson, 2009; Liu and Douthwaite, 2002).…”

Clarithromycin Exerts an Antibiofilm Effect againstSalmonella typhimuriumrdar Biofilm Formation, and Transforms the Physiology towards an Apparent Oxygen-depleted Energy and Carbon Metabolism

“…Macrolides, a class of broad-spectrum antibiotics, were the third class of antibiotics to be discovered used since 1952 in clinical practice. Erythromycin, the first discovered natural macrolide, has thereby been replaced by the more effective second generation semi-synthetic macrolides clindamycin and azithromycin (17). Macrolides selectively inhibit protein biosynthesis by binding to the 23S RNA of the 50 S subunit of the ribosome, halting translation in bacteria mainly by blocking the entrance tunnel for the nascent peptide chain (18,19,20,21).…”