Synthetic group A streptogramin antibiotics that overcome Vat resistance

Abstract

Natural products serve as chemical blueprints for the majority of antibiotics in our clinical arsenal. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class 1 . Virginiamycin acetyltransferases (Vats) are resistance proteins that provide protection against streptogramins 2 , potent Gram-positive antibiotics that inhibit the bacterial ribosome 3 . Due to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogs that overcome Vat resistance have not been previously accessed 2 . Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with unprecedented structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogs to the bacterial ribosome at high resolution, revealing new binding interactions that extend into the peptidyl tRNA binding site and towards synergistic binders that occupy the nascent peptide exit tunnel (NPET). One of these analogs has excellent activity against several streptogramin-resistant strains of S. aureus , exhibits decreased acetylation rates in vitro , and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.

Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance

“…Altogether, our structural study uncovering the molecular mechanism of Erm-mediated resistance could be a starting point for the rational knowledge-based development of new MLS B antibiotics active against challenging drug-resistant pathogens. This quest will be likely additionally stimulated by the recently discovered new combinatorial approaches for the synthesis of novel macrolides 47 , streptogramins 48 , and other drugs. Interestingly, all previous attempts to make macrolides active against Erm-modified ribosomes relied on derivatization of the existing macrolides to provide additional anchoring points that improved their overall affinity 49 .…”

A synthetic antibiotic class overcoming bacterial multidrug resistance

“…For decades, natural products have served as both conceptual and material starting points for antibiotics discovery, but making specific chemical modifications to structurally complex natural products (that is, semisynthesis) is inherently challenging, and the pace of drug discovery by this route has slowed markedly 2 . In an alternative approach, the development of fully synthetic platforms to construct tetracycline 4 , macrolide 5 , 6 , group A streptogramin 7 and arylomycin 8 antibiotics has enabled deep-seated structural modifications that are not achievable by semisynthesis. These technologies enable chemists to envision and reduce to practice an almost limitless array of design hypotheses.…”

Present and Future Perspectives on Therapeutic Options for Carbapenemase-Producing Enterobacterales Infections

“…After modifying and assembling these molecular LEGO pieces, it was observed that these variations had antimicrobial activity against a wide range of pathogens, including streptogramin-resistant S. aureus . Therefore, the synthesis and assembly of slightly modified modules can revitalize several antibiotics classes that have been abandoned due to the natural mechanisms of bacterial resistance, offering new hopes in the war against CRE [ 252 ]. Another LEGO-like approach is expected to revitalize endolysins, enzymes employed by bacteriophages to produce cell lysis and virion release, and currently used in the therapeutic management of Gram-negative bacteria [ 253 ].…”