Selectively Guanidinylated Aminoglycosides as Antibiotics

Abstract

The emergence of virulent, drug-resistant bacterial strains coupled with a minimal output of new pharmaceutical agents to combat them makes this a critical time for antibacterial research. Aminoglycosides are a well-studied, highly potent class of naturally occurring antibiotics with scaffolds amenable to modification, and therefore, they provide an excellent starting point for the development of semisynthetic, next-generation compounds. To explore the potential of this approach, we synthesized a small library of aminoglycoside derivatives selectively and minimally modified at one or two positions with a guanidine group replacing the corresponding amine or hydroxy functionality. Most guanidino-aminoglycosides showed increased affinity for the ribosomal decoding rRNA site, the cognate biological target of the natural products, when compared with their parent antibiotics, as measured by an in vitro fluorescence resonance energy transfer (FRET) A-site binding assay. Additionally, certain analogues showed improved minimum inhibitory concentration (MIC) values against resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An amikacin derivative holds particular promise with activity greater than or equal to the parent antibiotic in the majority of bacterial strains tested.

Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis: Old scaffolds for new perspectives in RNA targeting

“…The fact that its activity and specificity can be further optimized by chemical modification has been already proven in the past. 18,24,25,37,47,48 Most importantly, the comparison of aminoglycosides and tetracyclines allowed us to demonstrate that the site of the interaction on the pre-miRNA sequence/structure is of the utmost importance for the efficient inhibition of its processing by the enzyme Dicer. Macrolides and puromycin showed very good affinity for targeted RNAs but were not able to inhibit premiRNAs processing, while other antibiotics (lincosamides, linezolid and chloramphenicol) did not bind to pre-miRNAs and did not inhibit Dicer processing further demonstrating that selectivity can be achieved in the domain of RNA targeting using small molecules.…”

Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A‐Site Binding and Higher Potency against Resistant Bacteria

“…[12] Analogs with guanidinium groups replacing the 6″ hydroxyl have been shown to display increased A-site affinity and in some cases superior antibacterial activity. [13] This suggests that certain modifications to the 6″ position may indeed increase the affinity for the A-site and confer desirable antibacterial efficacy. We set out to test this hypothesis by making derivatives of both 1a and 2a with a variety of substituents differing in size, basicity, and in number of hydrogen bond donors and acceptors.…”

“…[13,14] The synthetic approach for the conversion of the parent aminoglycosides into these intermediates is illustrated with tobramycin ( 1a ) in Scheme 1). First, all amines were globally tert -butyloxycarbonyl (Boc)-protected using di- tert -butyl dicarbonate.…”

Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D)

“…As a consequence, many antibiotics have been rendered ineffective and there is now an urgent need for new classes of antibiotics to combat multi-drug resistant (MDR) organisms [1]. Aminoglycosides were first introduced as antibacterial therapeutics in the 1940's as they showed activities towards both Gram-negative and Gram-positive bacteria [2].…”