Streptogramins

Abstract: Macrolides are composed of 14 (erythromycin and clarithromycin)-, 15 (azithromycin)-, or 16 (josamycin, spiramycin, and tylosin)-membered lactones to which are attached amino and/or neutral sugars via glycosidic bonds. Erythromycin was introduced in 1952 as the first macrolide antibiotic. Unfortunately, within a year, erythromycin-resistant (Emr) staphylococci from the United States, Europe, and Japan were described (101). Erythromycin is produced by Saccharopolyspora erythraea, while the newer macrolides are semisynthetic molecules with substitutions on the lactone. The newer derivatives, such as clarithromycin and azithromycin, have improved intracellular and tissue penetration, are more stable, are better absorbed, have a lower incidence of gastrointestinal side effects, and are less likely to interact with other drugs. They are useable against a wider range of infectious bacteria, such as Legionella, Chlamydia, Haemophilus, and some Mycobacterium species (not M. tuberculosis), and their pharmacokinetics provide for less frequent dosing than erythromycin (21, 47, 96, 97). As a result, the usage of the newer macrolides has increased dramatically over the last few years, which has led to increased exposure of bacterial populations to macrolides (101–103, 107). Macrolides inhibit protein synthesis by stimulating dissociation of the peptidyl-tRNA molecule from the ribosomes during elongation (101, 103). This results in chain termination and a reversible stoppage of protein synthesis. The first mechanism of macrolide resistance described was due to posttranscriptional modification of the 23S rRNA by the adenine-N6 methyltransferase (101–103). These enzymes add one or two methyl groups to a single adenine (A2058 in Escherichia coli) in the 23S rRNA moiety. Over the last 30 years, a number of adenine-N6-methyltransferases from different species, genera, and isolates have been described. In general, genes encoding these methylases have been designated erm (erythromycin ribosome methylation), although there are exceptions, especially in the antibiotic-producing organisms (see Tables ​Tables11 and ​and3)3) (103). As the number of erm genes described has grown, the nomenclature for these genes has varied and has been inconsistent (Table ​(Table1).1). In some cases, unrelated genes have been given the same letter designation, while in other cases, highly related genes (>90% identity) have been given different names. TABLE 1 rRNA methylase genes involved in MLSB resistance TABLE 3 Location of antibiotic resistance genesa The binding site in the 50S ribosomal subunit for erythromycin overlaps the binding site of the newer macrolides, as well as the structurally unrelated lincosamides and streptogramin B antibiotics. The modification by methylase(s) reduces the binding of all three classes of antibiotics, which results in resistance against macrolides, lincosamides, and streptogramin B antibiotics (MLSB). The rRNA methylases are the best studied among macrolide resistance mechanisms (47, 101–103). However, a variety of other mechanisms have been described which also confer resistance (Table ​(Table2).2). Many of these alternative mechanisms of resistance confer resistance to only one or two of the antibiotic classes of the MLSB complex. TABLE 2 Efflux and inactivating genes In this review, we suggest a new nomenclature for naming MLS genes and propose to use the rules developed for identifying and naming new tetracycline resistance genes (51, 52). This system, with a few recent modifications, was originally designed because of the ability of two genes to be distinguished uniquely by DNA-DNA probe methodology (51). It was generally found that two genes with <80% amino acid sequence identity provided enough variability in nucleotide sequence to permit distinct probes to be designed. Although many investigators are likely to sequence new genes, the use of probe technology allows rapid identification of isolates containing potentially new genes, as well as a reliable way to screen populations and determine the frequency of any one resistant determinant. Therefore, we continued this paradigm by assigning two genes of ≥80% amino acid identity to the same class and same letter designation, while two genes that show ≤79% amino acid identity are given a different letter designation. Table ​Table11 shows the results of the classification, with some classes having members with little variability, while others, like classes A and O, show a greater range of homology at both the DNA and amino acid levels. As new gene sequences emerge, ideally they will need to be compared by oligonucleotide probe hybridization and/or sequence analysis against the bank of known genes before a new designation is assigned. If multiple genes are available in any one class, especially when there is a range as in class A, then all representative members of the class should be examined, not just one. To confirm that the proposed name or number for the newly discovered resistance determinant has not been used by another investigator, please contact M. C. Roberts for this information. A similar request has been made for new tet genes (52).

Abstract: Images

Abstract: In this article we briefly review theories about the ecological roles of microbial secondary metabolites and discuss the prevalence of multiple secondary metabolite production by strains of Streptomyces, highlighting results from analysis of the recently sequenced Streptomyces coelicolor and Streptomyces avermitilis genomes. We address this question: Why is multiple secondary metabolite production in Streptomyces species so commonplace? We argue that synergy or contingency in the action of individual metabolites against biological competitors may, in some cases, be a powerful driving force for the evolution of multiple secondary metabolite production. This argument is illustrated with examples of the coproduction of synergistically acting antibiotics and contingently acting siderophores: two well-known classes of secondary metabolite. We focus, in particular, on the coproduction of β-lactam antibiotics and β-lactamase inhibitors, the coproduction of type A and type B streptogramins, and the coregulated production and independent uptake of structurally distinct siderophores by species of Streptomyces. Possible mechanisms for the evolution of multiple synergistic and contingent metabolite production in Streptomyces species are discussed. It is concluded that the production by Streptomyces species of two or more secondary metabolites that act synergistically or contingently against biological competitors may be far more common than has previously been recognized, and that synergy and contingency may be common driving forces for the evolution of multiple secondary metabolite production by these sessile saprophytes.

Abstract: The relative frequency of 10 determinants of resistance to macrolides, lincosamides, and streptogramins was investigated by PCR in a series of 294 macrolide-, lincosamide-, and/or streptogramin-resistant clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci isolated in 1995 from 32 French hospitals. Resistance was mainly due to the presence of ermA or ermC genes, which were detected in 259 strains (88%), in particular those resistant to methicillin (78% of the strains). Macrolide resistance due to msrA was more prevalent in coagulase-negative staphylococci (14.6%) than in S. aureus (2.1%). Genes related to linA/linA' and conferring resistance to lincomycin were detected in one strain of S. aureus and seven strains of coagulase-negative staphylococci. Resistance to pristinamycin and quinupristin-dalfopristin was phenotypically detected in 10 strains of S. aureus and in three strains of coagulase-negative staphylococci; it was always associated with resistance to type A streptogramins encoded by vat or vatB genes and occurred in association with erm genes. The vga gene conferring decreased susceptibility to type A streptogramins was present alone in three strains of coagulase-negative staphylococci and in combination with erm genes in 10 strains of coagulase-negative staphylococci. A combination of vga-vgb-vat and ermA genes was found in a single strain of S. epidermidis.