SummaryLinezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of cfr likely involves protection against natural antibiotics whose site of action overlaps that of linezolid. In the chromosome of the clinical strain, cfr is linked to ermB, a gene responsible for dimethylation of A2058 in 23S rRNA. Coexpression of these two genes confers resistance to all the clinically relevant antibiotics that target the large ribosomal subunit. The association of the ermB/cfr operon with transposon and plasmid genetic elements indicates its possible mobile nature. This is the first example of clinical resistance to the synthetic drug linezolid which involves a natural resistance gene with the capability of disseminating among Gram-positive pathogenic strains.

A2503 in 23S rRNA of the Gram-negative bacterium Escherichia coli is located in a functionally important region of the ribosome, at the entrance to the nascent peptide exit tunnel. In E. coli, and likely in other species, this adenosine residue is posttranscriptionally modified to m 2 A. The enzyme responsible for this modification was previously unknown. We identified E. coli protein YfgB, which belongs to the radical SAM enzyme superfamily, as the methyltransferase that modifies A2503 of 23S rRNA to m 2 A. Inactivation of the yfgB gene in E. coli led to the loss of modification at nucleotide A2503 of 23S rRNA as revealed by primer extension analysis and thin layer chromatography. The A2503 modification was restored when YfgB protein was expressed in the yfgB knockout strain. A similar protein was shown to catalyze post-transcriptional modification of A2503 in 23S rRNA in Gram-positive Staphylococcus aureus. The yfgB knockout strain loses in competition with wild type in a co-growth experiment, indicating functional importance of A2503 modification. The location of A2503 in the exit tunnel suggests its possible involvement in interaction with the nascent peptide and raises the possibility that its post-transcriptional modification may influence such an interaction.

Nanoparticles (NPs)-hydrogel composite (nanogels) have yielded a surge in the design and development of novel drug delivery systems for the treatment of many ailments, including periodontal disease. The recent innovations in nanotechnological drug carrier systems seem promising, as it provides a means to improve the bioavailability of poorly soluble drugs, formulations of controlled and targeted drug delivery systems, and drug release control based on the stimuli response, among others. Several polymeric NPs-hydrogel coformulations have been investigated during the last few years, mostly using synthetic and natural polymers. Some of the results and rewards achieved from these novel approaches are the use of bioadhesive polymers to achieve prolonged drug release, the increment of intra-pocket drug penetration, the enhancement of mechanical properties using chemical crosslinkers, and the possibility of loading multiple drugs in a unit delivery system. Furthermore, these nanotechnological advances have also shown that NPs possess great potential as drug carriers in periodontal disease treatment. The future utilization of these advantages will significantly improve dental care. The coformulation of NPs-hydrogel composite will yield additional benefits that are much greater than ordinary NPs or hydrogels in delivering of drug into the periodontal pockets. The aim of this review article is to summarize updates on the current and future nanotechnological approaches that are being investigated for the treatment of periodontitis, with particular attention to the nanogels, and to identify arenas which its exploration might lead to the development of effective intra-pocket drug delivery systems for the treatment of periodontal diseases. The review also provides brief applications of nanogels in the management of other diseases.