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In vitro activity of DX-619, a novel des-fluoro(6) quinolone, against a panel of Streptococcus pneumoniae mutants with characterized resistance mechanisms.

ABSTRACT: The in vitro activities of DX-619 and four other quinolones were compared against Streptococcus pneumoniae mutants that contained a variety of alterations within the quinolone resistance-determining regions. DX-619 was the most potent quinolone and was least affected by the mutations.

SUBMITTER: Wickman PA

PROVIDER: S-EPMC1366926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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DX-619, a novel des-fluoro(6) quinolone manifesting low frequency of selection of resistant Staphylococcus aureus mutants: quinolone resistance beyond modification of type II topoisomerases.

Project description:DX-619, a novel des-fluoro(6) quinolone, was 16- to 32-fold, twofold, and four- to eightfold more potent than ciprofloxacin, gemifloxacin, and garenoxacin, respectively, against wild-type Staphylococcus aureus. DX-619 manifested equal fourfold increases in MIC against a common parC mutant and a common gyrA mutant and selected for mutants at up to two- to fourfold its MIC, consistent with dual-targeting properties. Of the four independent single-step mutants selected, two had new single mutations in parC (V87F and R17H), and two shared a new gyrA mutation (A26V), one with an additional deletion mutation in parE (delta215-7). By allelic exchange, the ParC but not the GyrA or ParE mutation was shown to be fully responsible for the resistance phenotypes, suggesting an as yet undefined mechanism of resistance operating in conjunction with type II topoisomerase mutations contributed to resistance to DX-619. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that DX-619 had similar activity against topoisomerase IV and gyrase (50% stimulation of cleavage complexes concentration, 1.25 and 0.62 to 1.25 mug/ml, respectively). Susceptibility studies with DX-619 and an array of efflux pump substrates with and without reserpine, an inhibitor of efflux pumps, suggested that resistance in DX-619-selected mutants is affected by mechanisms other than mutations in topoisomerases or known reserpine-inhibitable pumps in S. aureus and thus are likely novel.

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Activity of DX-619 compared to other agents against viridans group streptococci, Streptococcus bovis, and Cardiobacterium hominis.

Project description:Against 198 viridans group streptococci, 25 Streptococcus bovis strains, and 5 Cardiobacterium hominis strains, MICs of DX-619, a des-F(6)-quinolone, were between 0.004 and 0.25 microg/ml. These MICs were lower than those of other quinolones (< or = 0.008 to > 32 microg/ml). Beta-lactam MICs were between < or = 0.008 and 16 microg/ml. Azithromycin resistance was found in most species, while most were telithromycin susceptible. Glycopeptides and linezolid were active against viridans group strains but inactive against C. hominis.

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Activity of BMS-284756, a novel des-fluoro(6) quinolone, against Staphylococcus aureus, including contributions of mutations to quinolone resistance.

Project description:The in vitro activity of BMS-284756 against 602 Staphylococcus aureus isolates, including 152 that were both methicillin and ciprofloxacin resistant (MIC > or = 4 microg/ml), was determined. For ciprofloxacin-susceptible and nonsusceptible isolates, the MICs at which 50% of organisms were inhibited were 0.015 and 2 microg/ml and the MICs at which 90% of organisms were inhibited were 0.03 and 4 microg/ml, respectively.

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Altered lipid composition in Streptococcus pneumoniae cpoA mutants.

Project description:BACKGROUND: Penicillin-resistance in Streptococcus pneumoniae is mainly due to alterations in genes encoding the target enzymes for beta-lactams, the penicillin-binding proteins (PBPs). However, non-PBP genes are altered in beta-lactam-resistant laboratory mutants and confer decreased susceptibility to beta-lactam antibiotics. Two piperacillin resistant laboratory mutants of Streptococcus pneumoniae R6 contain mutations in the putative glycosyltransferase gene cpoA. The CpoA gene is part of an operon including another putative glycosyltransferase gene spr0982, both of which being homologous to glycolipid synthases present in other Gram-positive bacteria. RESULTS: We now show that the cpoA mutants as well as a cpoA deletion mutant are defective in the synthesis of galactosyl-glucosyl-diacylglycerol (GalGlcDAG) in vivo consistent with the in vitro function of CpoA as ?-GalGlcDAG synthase as shown previously. In addition, the proportion of phosphatidylglycerol increased relative to cardiolipin in cpoA mutants. Moreover, cpoA mutants are more susceptible to acidic stress, have an increased requirement for Mg(2+) at low pH, reveal a higher resistance to lysis inducing conditions and are hypersensitive to bacitracin. CONCLUSIONS: The data show that deficiency of the major glycolipid GalGlcDAG causes a pleitotropic phenotype of cpoA mutant cells consistent with severe membrane alterations. We suggest that the cpoA mutations selected with piperacillin are directed against the lytic response induced by the beta-lactam antibiotic.

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Isolation of Streptococcus pneumoniae biofilm mutants and their characterization during nasopharyngeal colonization.

Project description:Asymptomatic colonization of the nasopharynx by Streptococcus pneumoniae precedes pneumococcal disease, yet pneumococcal colonization factors remain poorly understood. Many bacterial infections involve biofilms which protect bacteria from host defenses and antibiotics. To gain insight into the genetics of biofilm formation by S. pneumoniae, we conducted an in vitro screen for biofilm-altered mutants with the serotype 4 clinical isolate TIGR4. In a first screen of 6,000 mariner transposon mutants, we repeatedly isolated biofilm-overproducing acapsular mutants, suggesting that the capsule was antagonistic to biofilm formation. Therefore, we screened 6,500 additional transposon mutants in an S. pneumoniae acapsular background. Following this approach, we isolated 69 insertions in 49 different genes. The collection of mutants includes genes encoding bona fide and putative choline binding proteins, adhesins, synthases of membrane and cell wall components, extracellular and cell wall proteases, efflux pumps, ABC and PTS transporters, and transcriptional regulators, as well as several conserved and novel hypothetical proteins. Interestingly, while four insertions mapped to rrgA, encoding a subunit of a recently described surface pilus, rrgB and rrgC (encoding the other two pilus subunits) mutants had no biofilm defects, implicating the RrgA adhesin but not the pilus structure per se in biofilm formation. To correlate our findings to the process of colonization, we transferred a set of 29 mutations into the wild-type encapsulated strain and then tested the fitness of the mutants in vivo. Strikingly, we found that 23 of these mutants were impaired for nasopharyngeal colonization, thus establishing a link between biofilm formation and colonization.

| S-EPMC2573321 | biostudies-literature

PCR-oligonucleotide ligation assay for detection of point mutations associated with quinolone resistance in Streptococcus pneumoniae.

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2024-08-19 | PXD054463 | Pride

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