The biosynthetic gene cluster (12.3 kb) of mersacidin, a lanthionine-containing antimicrobial peptide, is located on the chromosome of the producer, Bacillus sp. strain HIL Y-85,54728 in a region that corresponds to 348°on the chromosome of Bacillus subtilis 168. It consists of 10 open reading frames and contains, in addition to the previously described mersacidin structural gene mrsA (G. Bierbaum, H. Brötz, K.-P. Koller, and H.-G. Sahl, FEMS Microbiol. Lett. 127:121-126, 1995), two genes, mrsM and mrsD, coding for enzymes involved in posttranslational modification of the prepeptide; one gene, mrsT, coding for a transporter with an associated protease domain; and three genes, mrsF, mrsG, and mrsE, encoding a group B ABC transporter that could be involved in producer self-protection. Additionally, three regulatory genes are part of the gene cluster, i.e., mrsR2 and mrsK2, which encode a two-component regulatory system which seems to be necessary for the transcription of the mrsFGE operon, and mrsR1, which encodes a protein with similarity to response regulators. Transcription of mrsA sets in at early stationary phase (between 8 and 16 h of culture).Mersacidin is a tetracyclic peptide that is produced by Bacillus sp. strain 54728 (9). It belongs to the family of lantibiotics, a group of lanthionine-containing peptides with antimicrobial activity (46). On the basis of differences in their structures, two types of lantibiotics have been distinguished, type A and type B lantibiotics (20). Mersacidin, actagardine, and the lantibiotics of the cinnamycin type constitute the latter group, which comprises rigid globular peptides with no net charge or a net negative charge. In contrast, type A lantibiotics are flexible, elongated peptides that act by forming pores in the bacterial membrane. Besides lanthionine, lantibiotics contain a number of rare amino acids, such as didehydroalanine, didehydrobutyrine, methyllanthionine, S-aminovinylcysteine, etc. In contrast to classical peptide antibiotics, lantibiotics are synthesized from precursor genes using the ribosomal pathway and the rare amino acids are introduced by posttranslational modification procedures into the lantibiotic precursor peptides. These so-called prepeptides consist of an N-terminal leader sequence and the C-terminal propeptide domain that is modified to be the lantibiotic. Several gene clusters of type A lantibiotics have been studied so far and found to comprise the structural gene, the enzymes that catalyze the modification reactions and accessory factors that confer export from the cell, regulation, and producer self-protection or immunity, a specific mechanism that protects the producing strain against the bactericidal action of its own lantibiotic (for recent reviews, see references 19 and 42). These gene clusters can be subdivided into two groups. The gene clusters of the strongly basic peptides, which possess a leader peptide with a conserved FNLD motif, contain two modification enzymes, LanB and LanC, involved in dehydration of hydroxy amino acids a...
DNA hybridization data and aminoglycoside resistance profiles (AGRPs) were determined for 4,088 clinical isolates from three studies (United States, Belgium, and Argentina). The correlation between susceptibility profiles and hybridization results was determined with nine DNA probes. For each of the seven aminoglycoside resistance profiles which we were able to test, the data suggested at least two distinct genes could encode enzymes which lead to identical resistance profiles. Furthermore, the DNA hybridization data showed that individual strains carried up to six unique aminoglycoside resistance genes. DNA hybridization revealed interesting differences in the frequencies of these genes by organism and by country.
The gene encoding a 6'-N-acetyltransferase, AAC(6')-II, was cloned from Pseudomonas aeruginosa plasmid pSCH884. This gene mediates resistance to gentamicin, tobramycin, and netilmicin but not amikacin or isepamicin. The DNA sequence of the gene and flanking regions was determined. The 5'- and 3'-flanking sequences showed near identity to sequences found abutting a variety of different genes encoding resistance determinants. It is likely that the current structure arose by the integration of the 572-base-pair sequence containing the AAC(6')-II gene into a Tn21-related sequence at the recombinational hot spot, AAAGTT. We have compared the sequence of the AAC(6')-II gene to genes of other 6'-N-acetyltransferases. An AAC(6')-Ib protein (encoded by the aacA4 gene; G. Tran Van Nhieu and E. Collatz, J. Bacteriol. 169:5708-5714, 1987) that results in resistance to amikacin but not gentamicin was found to share 82% sequence similarity with the AAC(6')-II protein. We speculate that these two genes arose from a common ancestor and that the processes of selection and dissemination have led to the observed differences in the spectrum of aminoglycoside resistance.
In vitro studies were performed with 74 Pseudomonas aeruginosa isolates which were collected during a multicenter trial. The isolates were obtained from 70 patients who had been treated with netilmicin as the only antipseudomonal antibiotic. Clinically Strains that produced aminoglycoside-inactivating enzymes were similarly affected by cations. Some strains with aminoglycoside permeability defects were also affected by the addition of calcium and magnesium cations, but other strains showed only modest increases in aminoglycoside MICs.When
The in vitro activities of three new 8-methoxychlortetracyclines, Sch 36969, 33256 and 34164 were compared to tetracycline, minocycline and doxycycline. Against aerobic Gramnegative rods Sch 36969 had a geometric mean MIC (GMM)of 4.2^g/ml, about 8-fold more potent than Sch 33256, and similar to all the other compounds. Sch 36969 also had good activity against methicillin-resistant (GMM, 0.21^g/ml) and -susceptible Staphylococci (GMM, 0.14 A*g/ml), Streptococci (GMM, 0.06^g/ml), and most anaerobic bacteria (GMM, <0.5 jug/ml). In general, Sch 36969 was similar to, or more potent than, all the other compounds tested.Serum levels of Sch 36969 in squirrel monkeys were 4-fold lower (AUC, 4.5 /ug>hours/ml) than those of chlortetracycline (AUC, 16.1^g-hours/ml). In mouse protection tests (PD50s) against various strains of bacteria, Sch 36969 was similar in activity to tetracycline, but up to 6-fold less active than chlortetracycline.The structure activity relationships for these new chlortetracyclines are described.
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