bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships between Respiration and Susceptibility to Azole Antifungals in
Candida glabrata
Authors: Brun Sophie , Aubry Christophe , Lima Osana , Filmon Robert , Bergès Thierry , Chabasse Dominique , Bouchara Jean-Philippe 
Published: February 2003

ABSTRACT

Over the past two decades, the incidence of infections due to
Candida glabrata
, a yeast with intrinsic low susceptibility to azole antifungals, has increased markedly. Respiratory deficiency due to mutations in mitochondrial DNA (mtDNA) associated with resistance to azoles frequently occurs in vitro in this species. In order to specify the relationships between respiration and azole susceptibility, the effects of respiratory chain inhibitors on a wild-type isolate of
C. glabrata
were evaluated. Respiration of blastoconidia was immediately blocked after extemporaneous addition of potassium cyanide, whereas a 4-h preincubation was required for sodium azide. Antifungal susceptibility determined by a disk diffusion method on Casitone agar containing sodium azide showed a significant decrease in the susceptibility to azoles. Biweekly subculturing on Casitone agar supplemented with sodium azide was therefore performed. This resulted after 40 passages in the isolation of a respiration-deficient mutant, as suggested by its lack of growth on glycerol-containing agar. This respiratory deficiency was confirmed by flow cytometric analysis of blastoconidia stained with rhodamine 123 and by oxygraphy. Moreover, transmission electron microscopy and restriction endonuclease analysis of the mtDNA of mutant cells demonstrated the mitochondrial origin of the respiratory deficiency. Finally, this mutant exhibited cross-resistance to all the azoles tested. In conclusion, blockage of respiration in
C. glabrata
induces decreased susceptibility to azoles, culminating in azole resistance due to the deletion of mtDNA. This mechanism could explain the induction of petite mutations by azole antifungals which have been demonstrated to act directly on the mitochondrial respiratory chain.
Quinolone-DNA Interaction: Sequence-Dependent Binding to Single-Stranded DNA Reflects the Interaction within the Gyrase-DNA Complex
Authors: Noble Christian G. , Barnard Faye M. , Maxwell Anthony 
Published: February 2003

ABSTRACT

We have investigated the interaction of quinolones with DNA by a number of methods to establish whether a particular binding mode correlates with quinolone potency. The specificities of the quinolone-mediated DNA cleavage reaction of DNA gyrase were compared for a number of quinolones. Two patterns that depended on the potency of the quinolone were identified. Binding to plasmid DNA was examined by measuring the unwinding of pBR322 by quinolones; no correlation with quinolone potency was observed. Quinolone binding to short DNA oligonucleotides was measured by surface plasmon resonance. The quinolones bound to both single- and double-stranded oligonucleotides in an Mg
2+
-dependent manner. Quinolones bound to single-stranded DNA with a higher affinity, and the binding exhibited sequence dependence; binding to double-stranded DNA was sequence independent. The variations in binding in the presence of metal ions showed that Mg
2+
promoted tighter, more specific binding to single-stranded DNA than softer metal ions (Mn
2+
and Cd
2+
). Single-stranded DNA binding by quinolones correlated with the in vitro quinolone potency, indicating that this mode of interaction may reflect the interaction of the quinolone with DNA in the context of the gyrase-DNA complex.
Low-Level Resistance to Rifampin in
Streptococcus pneumoniae
Authors: Meier Patricia Stutzmann , Utz Silvia , Aebi Suzanne , Mühlemann Kathrin 
Published: February 2003

ABSTRACT

Rifampin is recommended for combination therapy of meningitis due to β-lactam-resistant
Streptococcus pneumoniae
. High-level rifampin resistance (MIC, ≥4 mg/liter) has been mapped to point mutations in clusters I and III of
rpoB
of the pneumococcus. The molecular basis of low-level resistance (MICs, ≥0.5 and <4 mg/liter) was analyzed. Spontaneous mutants of clinical pneumococcal isolates were selected on Columbia sheep blood agar plates containing rifampin at 0.5, 4, 10, or 50 mg/liter. Low-level resistance could be assigned to mutations in cluster II (I
545
N, I
545
L). Sensitive (MIC, <0.048 mg/liter) wild-type strains acquired low-level resistance at a rate approximately 10 times higher than that at which they acquired high-level resistance (average mutation frequencies, 2.4 × 10
−7
for low-level resistance versus 2.9 × 10
−8
for high-level resistance [
P
< 0.0001]). In second-step experiments, the frequencies of mutations from low- to high-level resistance were over 10 times higher than the frequencies of mutations from susceptibility to high-level resistance (average mutation frequencies, 7.2 × 10
−7
versus 5.0 × 10
−8
[
P
< 0.001]). Mutants with low-level resistance were stable upon passage. Sequencing of a clinical isolate with low-level resistance (MIC, 0.5 mg/liter) revealed a Q
150
R mutation upstream of cluster I. The frequencies of mutations to high-level resistance for this strain were even higher than the rates observed for the in vitro mutants. Therefore, a resistance-mediating mutation located outside clusters I, II, and III has been described for the first time in the pneumococcus. In vitro low-level rifampin resistance in
S. pneumoniae
could be mapped to cluster II of
rpoB
. Mutants of pneumococcus with low-level resistance may be selected in vivo during therapy in tissue compartments with low antibiotic concentrations and play a role in the development of resistance.
Resistance Genes of Aminocoumarin Producers: Two Type II Topoisomerase Genes Confer Resistance against Coumermycin A1and Clorobiocin
Authors: Schmutz Elisabeth , Mühlenweg Agnes , Li Shu-Ming , Heide Lutz 
Published: February 2003

ABSTRACTThe aminocoumarin resistance genes of the biosynthetic gene clusters of novobiocin, coumermycin A1, and clorobiocin were investigated. All three clusters contained agyrBRresistance gene, coding for a gyrase B subunit. Unexpectedly, the clorobiocin and the coumermycin A1clusters were found to contain an additional, similar gene, namedparYR. Its predicted gene product showed sequence similarity with the B subunit of type II topoisomerases. Expression ofgyrBRand likewise ofparYRinStreptomyces lividansTK24 resulted in resistance against novobiocin and coumermycin A1, suggesting that both gene products are able to function as aminocoumarin-resistant B subunits of gyrase. Southern hybridization experiments showed that the genome of all three antibiotic producers and ofStreptomyces coelicolorcontained two additional genes which hybridized with eithergyrBRorparYRand which may code for aminocoumarin-sensitive GyrB and ParY proteins. Two putative transporter genes,novAandcouR5, were found in the novobiocin and the coumermycin A1cluster, respectively. Expression of these genes inS. lividansTK24 resulted in moderate levels of resistance against novobiocin and coumermycin A1, suggesting that these genes may be involved in antibiotic transport.
Prevalence of Tetracycline Resistance Genes in Oral Bacteria
Authors: Villedieu A. , Diaz-Torres M. L. , Hunt N. , McNab R. , Spratt D. A. , Wilson M. , Mullany P. 
Published: February 2003

ABSTRACT

Tetracycline is a broad-spectrum antibiotic used in humans, animals, and aquaculture; therefore, many bacteria from different ecosystems are exposed to this antibiotic. In order to determine the genetic basis for resistance to tetracycline in bacteria from the oral cavity, saliva and dental plaque samples were obtained from 20 healthy adults who had not taken antibiotics during the previous 3 months. The samples were screened for the presence of bacteria resistant to tetracycline, and the tetracycline resistance genes in these isolates were identified by multiplex PCR and DNA sequencing. Tetracycline-resistant bacteria constituted an average of 11% of the total cultivable oral microflora. A representative 105 tetracycline-resistant isolates from the 20 samples were investigated; most of the isolates carried tetracycline resistance genes encoding a ribosomal protection protein. The most common
tet
gene identified was
tet
(M), which was found in 79% of all the isolates. The second most common gene identified was
tet
(W), which was found in 21% of all the isolates, followed by
tet
(O) and
tet
(Q) (10.5 and 9.5% of the isolates, respectively) and then
tet
(S) (2.8% of the isolates). Tetracycline resistance genes encoding an efflux protein were detected in 4.8% of all the tetracycline-resistant isolates; 2.8% of the isolates had
tet
(L) and 1% carried
tet
(A) and
tet
(K) each. The results have shown that a variety of tetracycline resistance genes are present in the oral microflora of healthy adults. This is the first report of
tet
(W) in oral bacteria and the first report to show that
tet
(O),
tet
(Q),
tet
(A), and
tet
(S) can be found in some oral species.
Diversity of Tetracycline Resistance Genes in Bacteria from Chilean Salmon Farms
Authors: Miranda Claudio D. , Kehrenberg Corinna , Ulep Catherine , Schwarz Stefan , Roberts Marilyn C. 
Published: February 2003

ABSTRACT

Twenty-five distinct tetracycline-resistant gram-negative bacteria recovered from four Chilean fish farms with no history of recent antibiotic use were examined for the presence of tetracycline resistance (
tet
) genes. Sixty percent of the isolates carried 1 of the 22 known
tet
genes examined. The distribution was as follows. The
tet
(A) gene was found in six isolates. The
tet
(B) gene was found in two isolates, including the first description in the genus
Brevundimonas
. Two isolates carried the
tet
(34) and
tet
(B) genes, including the first description of the
tet
(34) gene in
Pseudomonas
and
Serratia
and the first description of the
tet
(B) gene in
Pseudomonas
. The
tet
(H) gene was found in two isolates, which includes the first description in the genera
Moraxella
and
Acinetobacter
. One isolate carried
tet
(E), and one isolate carried
tet
(35), the first description of the gene in the genus
Stenotrophomonas
. Finally, one isolate carried
tet
(L), found for the first time in the genus
Morganella
. By DNA sequence analysis, the two
tet
(H) genes were indistinguishable from the previously sequenced
tet
(H) gene from Tn
5706
found in
Pasteurella multocida
. The
Acinetobacter radioresistens
isolate also harbored the Tn
5706
-associated 1,063-bp IS element IS
1597
, while the
Moraxella
isolate carried a 1,026-bp IS-like element whose 293-amino-acid transposase protein exhibited 69% identity and 84% similarity to the transposase protein of IS
1597
, suggesting the presence of a novel IS element. The distribution of
tet
genes from the Chilean freshwater ponds was different than those that have previously been described from other geographical locations, with 40% of the isolates carrying unidentified tetracycline resistance genes.
New Anti-Human Immunodeficiency Virus Type 1 6-Aminoquinolones: Mechanism of Action
Authors: Parolin Cristina , Gatto Barbara , Del Vecchio Claudia , Pecere Teresa , Tramontano Enzo , Cecchetti Violetta , Fravolini Arnaldo , Masiero Sara , Palumbo Manlio , Palù Giorgio 
Published: February 2003

ABSTRACTA 6-aminoquinolone derivative, WM5, which bears a methyl substituent at the N-1 position and a 4-(2-pyridyl)-1-piperazine moiety at position 7 of the bicyclic quinolone ring system, was previously shown to exhibit potent activity against replication of human immunodeficiency virus type 1 (HIV-1) in de novo-infected human lymphoblastoid cells (V. Cecchetti et al., J. Med. Chem. 43:3799-3802, 2000). In this report, we further investigated WM5's mechanism of antiviral activity. WM5 inhibited HIV-1 replication in acutely infected cells as well as in chronically infected cells. The 50% inhibitory concentrations were 0.60 ± 0.06 and 0.85 ± 0.05 μM, respectively. When the effects of WM5 on different steps of the virus life cycle were analyzed, the reverse transcriptase activity and the integrase and protease activities were not impaired. By using a transienttrans-complementation assay to examine the activity of WM5 on the replicative potential of HIV-1 in a single round of infection, a sustained inhibition of Tat-mediated long terminal repeat (LTR)-driven transcription (>80% of controls) was obtained in the presence of 5 μM WM5. Interestingly, the aminoquinolone was found to efficiently complex TAR RNA, with a dissociation constant in the nanomolar range (19 ± 0.6 nM). These data indicate that WM5 is a promising lead compound for the development of a new class of HIV-1 transcription inhibitors characterized by recognition of viral RNA target(s).
Cefpodoxime-Proxetil versus Trimethoprim-Sulfamethoxazole for Short-Term Therapy of Uncomplicated Acute Cystitis in Women
Authors: Kavatha Demetra , Giamarellou Helen , Alexiou Zoe , Vlachogiannis Nickolas , Pentea Stavroula , Gozadinos Thomas , Poulakou Garyphalia , Hatzipapas Agissilaos , Koratzanis George 
Published: February 2003

ABSTRACT

One hundred sixty-three women with uncomplicated acute lower urinary tract infections were included in a multicenter randomized study comparing cefpodoxime-proxetil (one 100-mg tablet twice daily) with trimethoprim-sulfamethoxazole (one double-strength tablet [160/800 mg] twice daily) for 3 days. A total of 30 women in both arms were excluded from the study for various reasons. At 4 to 7 days after the discontinuation of therapy, 62 of 63 (98.4%) cefpodoxime-proxetil recipients and 70 of 70 (100%) trimethoprim-sulfamethoxazole patients were clinically cured and demonstrated bacteriological eradication, respectively. At 28 days after treatment, 48 of 55 (87.3%) and 43 of 50 (86%) cefpodoxime-proxetil recipients as well as 51 of 60 (85%) and 42 of 50 (84%) trimethoprim-sulfamethoxazole recipients were clinically cured and demonstrated bacteriological eradication, respectively. Independently of the prescribed regimen, a significant difference (
P
< 0.001) in failure rates was observed only for patients with a previous history of three or more episodes of acute cystitis per year. With the exception of one patient in the trimethoprim-sulfamethoxazole arm who discontinued therapy because of gastrointestinal pain, both antimicrobials were well tolerated. In conclusion, cefpodoxime-proxetil treatment for 3 days was as safe and effective as trimethoprim-sulfamethoxazole for 3 days for the treatment of uncomplicated acute cystitis in women.
Short-Course Artesunate Treatment of Uncomplicated
Plasmodium falciparum
Malaria in Gabon
Authors: Borrmann Steffen , Adegnika Ayola A. , Missinou Michel A. , Binder Ronald K. , Issifou Saadou , Schindler Andreas , Matsiegui Pierre-Blaise , Kun Jürgen F. J. , Krishna Sanjeev , Lell Bertrand , Kremsner Peter G. 
Published: February 2003

ABSTRACT

Artesunate is one of the most important antimalarial agents available, since it is effective against parasites that have developed resistance to conventional antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have been proposed. However, the efficacy of a 3-day course of artesunate alone has never been evaluated in individuals in Africa (which has 90% of the worldwide malaria burden) living in regions of hyperendemicity, where a considerable degree of immunity might substantially enhance the efficacy of short courses of artesunate compared to those in regions where the levels of endemicity are low. This lack of information does not permit a systematic assessment of the value of artesunate-based combination chemotherapies in Africa. Therefore, we studied the efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight, orally, once daily) for the treatment of uncomplicated
Plasmodium falciparum
malaria in Gabonese patients aged 4 to 15 years (
n
= 50). Artesunate was well tolerated, and no severe adverse event was reported. Parasite elimination was rapid and was achieved in all patients within ≤72 h (geometric mean time to elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50 patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that a 3-day course of artesunate fails to achieve sufficiently high cure rates for uncomplicated falciparum malaria in Gabonese children.
Synergistic Activity of Colistin and Ceftazidime against Multiantibiotic-Resistant
Pseudomonas aeruginosa
in an In Vitro Pharmacodynamic Model
Authors: Gunderson Brent W. , Ibrahim Khalid H. , Hovde Laurie B. , Fromm Timothy L. , Reed Michael D. , Rotschafer John C. 
Published: February 2003

ABSTRACT

Despite the marketing of a series of new antibiotics for antibiotic-resistant gram-positive bacteria, no new agents for multiple-antibiotic-resistant gram-negative infections will be available for quite some time. Clinicians will need to find more effective ways to utilize available agents. Colistin is an older but novel antibiotic that fell into disfavor with clinicians some time ago yet still retains a very favorable antibacterial spectrum, especially for
Pseudomonas
and
Acinetobacter
spp. Time-kill curves for two strains of multiantibiotic-resistant
Pseudomonas aeruginosa
were generated after exposure to colistin alone or in combination with ceftazidime or ciprofloxacin in an in vitro pharmacodynamic model. MICs of colistin, ceftazidime, ciprofloxacin, piperacillin-tazobactam, imipenem, and tobramycin were 0.125, ≥32, >4, >128/4, 16, and >16 mg/liter, respectively. Colistin showed rapid, apparently concentration-dependent bactericidal activity at concentrations between 3 and 200 mg/liter. We were unable to detect increased colistin activity at concentrations above 18 mg/liter due to extremely rapid killing. The combination of colistin and ceftazidime was synergistic (defined as at least a 2-log
10
drop in CFU per milliliter from the count obtained with the more active agent) at 24 h. Adding ciprofloxacin to colistin did not enhance antibiotic activity. These data suggest that the antibacterial effect of colistin combined with ceftazidime can be maximized at a peak concentration of ≤18 mg/liter.
Activities of Garenoxacin (BMS-284756) and Other Agents against Anaerobic Clinical Isolates
Authors: Hecht David W. , Osmolski J. R. 
Published: February 2003

ABSTRACT

A total of 590 clinical isolates consisting of 33 species of both gram-positive and gram-negative anaerobes were collected from nine centers in the Chicago area in 1998-1999. The largest number of isolates (330 isolates, 56%) belonged to the
Bacteroides
group. Isolates were tested by agar dilution against garenoxacin (BMS-284756, T-3811 ME), trovafloxacin, moxifloxacin, clindamycin, imipenem, piperacillin-tazobactam, and cefoxitin. All but one species (2% of
Bacteroides vulgatus
isolates) were fully susceptible to piperacillin-tazobactam and imipenem. A number of species were resistant to clindamycin. Among the fluoroquinolones, garenoxacin and trovafloxacin had an MIC at which 90% of the isolates tested were inhibited of <4 μg/ml for all but two species (
Fusobacterium mortiferum
/
varium
and
Peptostreptococcus anaerobius
).
Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant
Mycobacterium tuberculosis
Authors: Ordway Diane , Viveiros Miguel , Leandro Clara , Bettencourt Rosário , Almeida Josefina , Martins Marta , Kristiansen Jette E. , Molnar Joseph , Amaral Leonard 
Published: February 2003

ABSTRACT

The phenothiazines chlorpromazine (CPZ) and thioridazine (TZ) have equal in vitro activities against antibiotic-sensitive and -resistant
Mycobacterium tuberculosis.
These compounds have not been used as anti-
M. tuberculosis
agents because their in vitro activities take place at concentrations which are beyond those that are clinically achievable. In addition, chronic administration of CPZ produces frequent severe side effects. Because CPZ has been shown to enhance the killing of intracellular
M. tuberculosis
at concentrations in the medium that are clinically relevant, we have investigated whether TZ, a phenothiazine whose negative side effects are less frequent and serious than those associated with CPZ, kills
M. tuberculosis
organisms that have been phagocytosed by human macrophages, which have nominal killing activities against these bacteria. Both CPZ and TZ killed intracellular antibiotic-sensitive and -resistant
M. tuberculosis
organisms when they were used at concentrations in the medium well below those present in the plasma of patients treated with these agents. These concentrations in vitro were not toxic to the macrophage, nor did they affect in vitro cellular immune processes. TZ thus appears to be a serious candidate for the management of a freshly diagnosed infection of pulmonary tuberculosis or as an adjunct to conventional antituberculosis therapy if the patient originates from an area known to have a high prevalence of multidrug-resistant
M. tuberculosis
isolates. Nevertheless, we must await the outcomes of clinical trials to determine whether TZ itself may be safely and effectively used as an antituberculosis agent.
In Vitro Activity of S-3578, a New Broad-Spectrum Cephalosporin Active against Methicillin-Resistant Staphylococci
Authors: Fujimura Takaji , Yamano Yoshinori , Yoshida Isamu , Shimada Jingoro , Kuwahara Shogo 
Published: February 2003

ABSTRACT

The in vitro antibacterial activity of S-3578, a new parenteral cephalosporin, against clinical isolates was evaluated. The MICs of the drug at which 90% of the isolates were inhibited were 4 μg/ml for methicillin-resistant
Staphylococcus aureus
(MRSA) and 2 μg/ml for methicillin-resistant
Staphylococcus epidermidis
, which were fourfold higher than and equal to those of vancomycin, respectively. The anti-MRSA activity of S-3578 was considered to be due to its high affinity for penicillin-binding protein 2a (50% inhibitory concentration, 4.5 μg/ml). In time-kill studies with 10 strains each of MRSA and methicillin-susceptible
S. aureus
, S-3578 caused more than a 4-log
10
decrease of viable cells on the average at twice the MIC after 24 h of exposure, indicating that it had potent bactericidal activity. Furthermore, in population analysis of MRSA strains with heterogeneous or homogeneous resistance to imipenem, no colonies emerged from about 10
9
cells on agar plates containing twice the MIC of S-3578, suggesting the low frequency of emergence of S-3578-resistant strains from MRSA. S-3578 was also highly active against penicillin-resistant
Streptococcus pneumoniae
(PRSP), with a MIC
90
of 1 μg/ml, which was comparable to that of ceftriaxone. S-3578 also had antibacterial activity against a variety of gram-negative bacteria including
Pseudomonas aeruginosa
, though its activity was not superior to that of cefepime. In conclusion, S-3578 exhibited a broad antibacterial spectrum and, particularly, had excellent activity against gram-positive bacteria including methicillin-resistant staphylococci and PRSP. Thus, S-3578 was considered to be worthy of further evaluation.