Mobile lincosamide resistance genes in staphylococci.

Lincosamide resistance in staphylococci is based on the expression of a number of genes which specify three major resistance mechanisms: (i) enzymatic inactivation by lincosamide nucleotidyltransferases, (ii) ribosome protection by ABC-F proteins, and (iii) methylation of the ribosomal target sites in the 23S rRNA by Cfr or Erm methylases. So far, only two lnu genes, lnu(A) and lnu(B), which code for different types of lincosamide nucleotidyltransferases, have been found in staphylococci. The ABC-F proteins are encoded by genes of the vga, lsa and sal classes. The corresponding proteins exhibit ATP-binding domains, but lack transmembrane regions. So far, vga(A) genes - including the variant genes vga(A)V and vga(A)LC -, vga(C) genes and vga(E) genes - including the variant gene vga(E)V -, the lsa genes lsa(B) and lsa(E), as well as the sal(A) gene have been identified in staphylococci. The aforementioned genes, except lsa(B), confer resistance not only to lincosamides, but also to pleuromutilins and streptogramin A. The cfr and erm genes code for methylases which target the adenine residues at positions 2503 and 2048 in the 23S rRNA, respectively. While the cfr gene confers resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A, the erm genes mediate resistance to macrolides, lincosamides and streptogramin B. Many of the aforementioned lincosamide resistance genes are located on either plasmids or transposons and as such, can easily be disseminated across strain, species, and genus boundaries. The co-location of other antimicrobial resistance genes on the same mobile genetic element facilitates co-selection and persistence of the lincosamide resistance genes under the selective pressure imposed by other antimicrobial agents.

Mobile macrolide resistance genes in staphylococci.

Macrolide resistance in staphylococci is based on the expression of a number of genes which specify four major resistance mechanisms: (i) target site modification by methylation of the ribosomal target site in the 23S rRNA, (ii) ribosome protection via ABC-F proteins, (iii) active efflux via Major Facilitator Superfamily (MFS) transporters, and (iv) enzymatic inactivation by phosphotransferases or esterases. So far, 14 different classes of erm genes, which code for 23S rRNA methylases, have been reported to occur in staphylococci from humans, animals and environmental sources. Inducible or constitutive expression of the erm genes depends on the presence and intactness of a regulatory region known as translational attenuator. The erm genes commonly confer resistance not only to macrolides, but also to lincosamides and streptogramin B compounds. In contrast, the msr(A) gene codes for an ABC-F protein which confers macrolide and streptogramin B resistance whereas the mef(A) gene codes for a Major Facilitator Superfamily protein that can export only macrolides. Enzymatic inactivation of macrolides may be due to the macrolide phosphotransferase gene mph(C) or the macrolide esterase genes ere(A) or ere(B). Many of these macrolide resistance genes are part of either plasmids, transposons, genomic islands or prophages and as such, can easily be transferred across strain, species and genus boundaries. The co-location of other antimicrobial or metal resistance genes on the same mobile genetic element facilitates co-selection and persistence of macrolide resistance genes under the selective pressure of metals or other antimicrobial agents.

NXL-103, a combination of flopristin and linopristin, for the potential treatment of bacterial infections including community-acquired pneumonia and MRSA.

Novexel is developing the novel, orally active, semisynthetic streptogramin NXL-103, which has potential therapeutic application in the treatment of community-acquired pneumonia, community- or hospital-acquired MRSA, vancomycin-resistant enterococcus, and acute bacterial skin and soft tissue infections. NXL-103 is a combination of streptogramin A:streptogramin B components, initially developed in a 70:30 dose ratio. In multiple in vitro studies, NXL-103 demonstrated potent activity against different types of bacteria, such as Staphylococcus aureus (including MRSA), Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecium, Enterococcus faecalis, Haemophilus influenzae and Haemophilus parainfluenzae. NXL-103 was not affected by the resistance profiles of bacteria against other commonly used antibiotics. In phase I clinical trials, NXL-103 achieved bactericidal levels in plasma and was generally well tolerated, with side effects primarily on the gastrointestinal system. The first phase II trial conducted to evaluate the efficacy of NXL-103 against community-acquired pneumonia revealed that the compound was comparable with amoxicillin. NXL-103 has promise to become an important agent in the treatment of community-acquired pneumonia and complex skin and soft tissue infections, pending further development.