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At least 19 recordsLinked to original sources
PubMed1993

Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms.

Resistance of tumor cells to doxorubicin is a multifactorial phenomenon. In the present investigation, the ability of resistance modifiers against different resistance mechanisms was analysed. Substances which block P-glycoprotein (P-170) function circumvented resistance of doxorubicin-resistant sarcoma 180 (S180) cells completely (verapamil, thioridazine) or partially (hycanthone), whereas inhibitors of glutathione S-transferase (ethacrynic acid, N-ethylmaleimide, buthionine sulfoximine), and protein kinase C (staurosporine, acridine orange) caused only a partial reversion of resistance. In contrast, an inhibitor of alkaline phosphatase (levamisole) did not overcome doxorubicin-resistance. These results indicate that P-glycoprotein blockers might be more effective to modulate doxorubicin-resistance of S180 cells as compared to other modifiers. Further investigations using other MDR cell lines are required to clarify the generality of these findings.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Interpretative reading: recognizing the unusual and inferring resistance mechanisms from resistance phenotypes.

If isolates are speciated and if a sufficient range of antibiotics is tested, underlying resistance mechanisms can often be inferred from the antibiogram data. This allows: (i) anomalous combinations of phenotype and organism to be reconsidered; (ii) prediction of further antibiotics that deserve testing; and (iii) the suppression of susceptibilities that are anomalous in the light of the inferred mechanism. This 'interpretative reading' is widely undertaken in France but is largely precluded in the UK by limited speciation and the testing of narrow ranges of antibiotics. Nevertheless, UK laboratories should be aware of: (i) grossly anomalous combinations of species and phenotype, demanding reference laboratory confirmation; (ii) useful indicator drugs, where resistance implies a mechanism conferring other resistances that may be less obvious in direct tests; and (iii) antibiotics that are prone to select resistant mutants of particular species during therapy. Details of these combinations of organism and resistance are presented. Relationships between antibiogram and mechanism are also presented to allow full interpretative reading for those testing wide panels of drugs versus speciated isolates.

Aminoglycosides↗
PubMed1982

Trapping of nonhydrolyzable cephalosporins by cephalosporinases in Enterobacter cloacae and Pseudomonas aeruginosa as a possible resistance mechanism.

Resistance to cefotaxime (CTA) and ceftriaxone (CTR) in Enterobacter cloacae and Pseudomonas aeruginosa was investigated in several strains which are susceptible or resistant to these agents. All strains produced a chromosomally mediated cephalosporinase of the Richmond type 1. beta-Lactamases in susceptible strains were inducible, whereas resistant strains produced the enzymes constitutively. CTA and CTR were very poor substrates but potent inhibitors of all enzymes. Binding to, rather than hydrolysis by, beta-lactamases was assumed to be a major reason for resistance, and combination experiments supported this assumption. Dicloxacillin, which did not inhibit the growth and which was a poor inducer but a strong inhibitor of these beta-lactamases, exerted strong synergistic activity when combined with CTA or CTR in strains which produced large amounts of beta-lactamase constitutively. Cefoxitin, on the other hand, poorly active alone, but a good inducer, strongly antagonized CTA or CTR in susceptible strains producing inducible enzymes. In marked contrast to CTA and CTR were the findings with cefsulodin. Cefsulodin was active against CTA- and CTR-resistant Pseudomonas, and its activity was hardly influenced by dicloxacillin or cefoxitin. Since cefsulodin was found to have a very low affinity for all cephalosporinases, these findings corroborate the assumption that binding of nonhydrolyzable cephalosporins, rather than hydrolysis by cephalosporinases, may play an important role in resistance to these agents and other newer cephalosporins in Enterobacteriaceae, as well as in other gram-negative bacteria.

Cephalosporinase↗
PubMed2001

The changing nature of aminoglycoside resistance mechanisms and prevalence of newly recognized resistance mechanisms in Turkey.

OBJECTIVE: To determine the most frequently occurring individual and combined resistance mechanisms in Gram-negative bacteria resistant to any of the clinically available aminoglycosides in Turkey, and to compare these mechanisms with those found in smaller, earlier studies. METHODS: Aminoglycoside resistance mechanisms in Gram-negative isolates resistant to either gentamicin, tobramycin, netilmicin or amikacin collected in different regions of Turkey were evaluated both phenotypically and genotypically using 12 aminoglycosides and up to 22 aminoglycoside resistance gene probes. RESULTS: Among 696 aminoglycoside-resistant Gram-negative bacteria, resistance rates were very high for gentamicin (94.5%), tobramycin (82.4%), netilmicin (53.6%), and amikacin (49.7%). Although isepamicin was the most active aminoglycoside against Gram-negative bacteria, increased resistance (29.7%) was found and resistance rates were higher than those in most of the other countries surveyed in earlier studies. The most common aminoglycoside resistance mechanisms (AAC(3)-II (GTN), AAC(6')-I (TNA), and ANT(2")-I (GT)) in the earlier studies were also found in the present isolates of Klebsiella spp., Enterobacter spp. and Escherichia coli, with increased complexity. In addition to these old mechanisms, two new aminoglycoside resistance mechanisms, namely AAC(6')-III (TNAI) and AAC(6')-IV (GTNA), were also found at significant frequencies (11.9% and 26.9%, respectively) in these isolates of Enterobacteriaceae (n = 435). Among the isolates of Pseudomonas spp. (n = 150), in addition to the increased complexity of enzymatic resistance mechanisms (AAC(3)-I (16.6%), AAC(6')-II (29.3%), AAC(6')-III (19.3%), ANT(2")-I (40%)), permeability resistance seemed to be responsible for the high rates of resistance to aminoglycosides. CONCLUSION: The results of this study indicated increased resistance to clinically available aminoglycosides, including isepamicin, even though it was the most active, as a result of both the presence of new aminoglycoside resistance mechanisms and the increased complexity of all mechanisms, including permeability resistance, particularly in Pseudomonas in Turkey.

Aminoglycosides↗
PubMed1990

[Studies on resistant mechanisms in the resistant bacteria to chlorhexidine. II. Chemical components of the cell membrane and the electron microscopical observation of cell surface structure of chlorhexidine-resistant bacteria].

The mechanisms of resistance of Serratia marcescens and Pseudomonas cepacia to chlorhexidine were studied. Leakage of the cellular component such as protein was observed in a chlorhexidine sensitive strain (S1) of S. marcescens when S1 was treated with chlorhexidine at 40 micrograms/ml concentration, while this phenomenon was not observed in a resistant strain (R1). The following observations were made concerning about cell surface structure in the chlorhexidine sensitive and resistant strains of S. marcescens by chemical analyses of membrane components and electron microscopical studies of the thin sections of the cells. (1) When the S1 strains was treated with chlorhexidine, the outer membrane of the cells formed a wrinkled surface with irregular blebs, and some of which broke out to form various sizes of granules. The R1 strain did not undergo such morphological changes under the same conditions used in the sensitive strain. (2) A prominent protein with apparent molecular weight of 45 K was found exclusively in the R1 strain of S. marcescens as major outer membrane protein, while it was not found in S1 strain. (3) There were no differences in the composition of phospholipids and the amount of 3-hydroxytetradecanoic acid between S1 and R1 strains of S. marcescens. In Pseudomonas cepacia PCJ1 which is resistant to chlorhexidine, 50 K protein was also observed as a major protein of outer membrane of the cells. In contrast to the strain, a mutant of the strain, #102 which was obtained from PCJ1 strain by the treatment with methanesulfonic acid ethylester, did not possess the 50 K protein in its outer membrane. These data suggested that outer membrane components of bacteria were related importantly in resistant mechanism.

Bacterial Proteins↗
PubMed1996

Correlation of molecular resistance mechanisms and phenotypic resistance levels in streptomycin-resistant Mycobacterium tuberculosis.

Quantitative susceptibility testing of clinical isolates of streptomycin-resistant Mycobacterium tuberculosis demonstrated that there is a close correlation between the molecular resistance mechanism and the in vitro activity of streptomycin: mutations in rpsL were mainly associated with high-level resistance, mutations in rrs were associated with an intermediate level of resistance, and streptomycin-resistant isolates with wild-type rpsL and rrs exhibited a low-level resistance phenotype. Investigations of streptomycin-resistant isolates with wild-type rpsL and rrs revealed that (i) there is no cross-resistance to other drugs and (ii) a permeability barrier may contribute to resistance, because resistance was significantly lowered in the presence of a membrane-active agent.

Antibiotics, Antitubercular↗
PubMed2004

Microbiology and drug resistance mechanisms of fully resistant pathogens.

The acquisition of vancomycin resistance by Gram-positive bacteria and carbapenem resistance by Gram-negative bacteria has rendered some hospital-acquired pathogens impossible to treat. The resistance mechanisms employed are sophisticated and very difficult to overcome. Unless alternative treatment regimes are initiated soon, our inability to treat totally resistant bacteria will halt other developments in medicine. In the community, Gram-positive bacteria responsible for pneumonia could become totally resistant leading to increased mortality from this common infection, which would have a more immediate impact on our current lifestyles.

Acinetobacter Infections↗
PubMed1997

[Drug resistance mechanism of doxorubicin-resistant human gastric cancer cells BGC-823/DOX].

To further investigate drug resistance mechanism of BGC-823/DOX, we analysed the amplication, transcription and overexpression of genes associated with drug resistance by Southern blot, RT-PCR, immunohisto clogical assay and the concentration of Doxorubicin in the cells by flow cytometry. The results showed that parent cells of BGC-823 were cell line with intrinsic drug resistance similar to the gastrointestinal tumors. Multidrug resistance was the main mechanism of drug resistance in BGC-823/DOX. There was a significant difference between the doxorubicin-resistant cells line from parent cells with intrinsic drug resistance and from parent cells without intrinsic drug resistance in drug resistance.

ATP-Binding Cassette Transporters↗
PubMed1998

Analysis of quinolone resistance mechanisms in a sparfloxacin-resistant clinical isolate of Neisseria gonorrhoeae.

BACKGROUND AND OBJECTIVES: Recently, a reduction in the susceptibility of clinical isolates of Neisseria gonorrhoeae to newer fluoroquinolones including sparfloxacin in vitro has been recognized in Japan. The quinolone resistance mechanisms in gonococcal isolates from a patient with clinical failure of sparfloxacin treatment was investigated. GOAL: To report a man with gonococcal urethritis in whom clinical failure of sparfloxacin treatment occurred and to examine the quinolone resistance mechanisms in gonococcal isolates from the patient. STUDY DESIGN: A man with gonococcal urethritis was treated with oral 100 mg sparfloxacin three times daily for 5 days. However, clinical failure of the sparfloxacin treatment was observed. The antimicrobial susceptibilities of pretreatment and posttreatment isolates to sparfloxacin and other agents were measured. To analyze quinolone resistance mechanisms in the set of isolates, DNA sequencing of the genes corresponding to the quinolone resistance-determining regions within the GyrA and ParC proteins was performed. We also assayed the intracellular sparfloxacin accumulation level in these gonococcal cells. Moreover, we performed pulsed-field gel electrophoresis analysis to determine whether the pretreatment and posttreatment isolates were isogenic. RESULTS: The minimum inhibitory concentration of sparfloxacin for the posttreatment isolate (4 micrograms/ml) was 16 times higher than that for the pretreatment isolate (0.25 microgram/ml). The pretreatment isolate contained three mutations, including a Ser-91 to Phe mutation and an Asp-95 to Asn mutation in GyrA and a Ser-88 to Pro mutation in ParC. The posttreatment isolate had four mutations, including the same three mutations and an additional Glu-91 to Gly mutation in ParC. The sparfloxacin accumulation level within 30 minutes in the posttreatment isolate was four times less than that in the pretreatment isolate. There were no differences in the pulsed-field gel electrophoresis patterns between the pretreatment and posttreatment isolates from the patient. CONCLUSIONS: The emergence of a fluoroquinolone-resistant N. gonorrhoeae isolate with multiple mutations involving GyrA and ParC reduced the response to sparfloxacin treatment. Multiple dosing and long-term treatment with sparfloxacin seems to induce a mutation in ParC and an alteration leading to reduced drug accumulation that contribute to increasing the fluoroquinolone resistance level.

Adult↗
PubMed2006

Old dogs that learn new tricks: modified antimicrobial agents that escape pre-existing resistance mechanisms.

Increasing numbers of resistant bacteria and decreasing numbers of efficient antimicrobial agents demand for the development of new highly potent antimicrobial agents. The two main directions for the development of new antimicrobial agents are either the development of completely novel antimicrobial agents, or the modification of already existing antimicrobial molecules. The second direction proved to be a more successful and cost-efficient way of generating new antimicrobial agents. For this, chemical modifications have been included which render the antimicrobial agents insensitive to prevalent bacterial resistance mechanisms. However, detailed knowledge of the resistance mechanisms is indispensable. Molecular analysis of resistance mechanisms provides the required data to identify critical target structures. Furthermore, modification of antimicrobial agents makes it possible to escape known resistance mechanisms. In this report, two examples for such successful developments, one from human medicine (telithromycin) and the other from veterinary medicine (florfenicol), are presented.

Animals↗
PubMed1998

Resistance mechanism of Acinetobacter spp. strains resistant to DW-116, a new quinolone.

DW-116 is a new fluoroquinolone antimicrobial agent with a broad spectrum. In order to elucidate the resistance mechanism to DW-116 in Acinetobacter spp. bacteria, total chromosomal DNA was isolated from 10 strains of Acinetobacter spp. resistant to DW-116. Quinolone resistance determinant region (QRDR) of DNA gyrase gene was amplified by PCR. The 345 bp nucleotide fragment yielded was inserted into pKF 3 which was used as the vector. Comparisons of the DNA sequences of 8 strains with that of the wild type strain revealed a Ser-83 to Leu mutation in mutants and all ten strains contained one silent mutation(T-->G) in QRDR. From Acinetobacter MB4-8 strain, DNA gyrase was isolated and purified, through no-vobiocin-sepharose, heparin-sepharose affinity column chromatography. The enzyme was composed of two subunits and the molecular mass of subunits A and B were 75.6 and 51.9 kDa, respectively. The supercoiling activity of the reconstituted DNA gyrase composed of subunit A from Acinetobacter MB4-8 and subunit B from E. coli was not inhibited by 128 micrograms/ml of ciprofloxacin. It might be said that one of the resistance mechanisms to DW-116 in A-cinetobacter MB4-8 was subunit A alteration of DNA gyrase.

Acinetobacter↗
PubMed2025

Transfer learning with multiomics integration and deep neural networks reveals drug resistance mechanisms in cancer.

Drug resistance remains one of the primary challenges in effective cancer therapy. In this study, we employed a deep neural network (DNN)-based transfer learning (TL) approach to predict drug response and uncover drug resistance mechanisms. We integrated gene expression, somatic mutation, and copy number aberration (CNA) data with drug response profiles using multi-omics integration (MI). We used the Genomics of Drug Sensitivity in Cancer (GDSC) data for training and incorporated drugs with same pathways into the training models. We then evaluated drug response predictions on independent in-vivo PDX Encyclopedia (PDX) and ex-vivo the Cancer Genome Atlas (TCGA) datasets. In addition, we conducted pathway enrichment analyses to elucidate the mechanisms underlying drug resistance for paclitaxel, 5-fluorouracil (5-FU), gemcitabine, and cetuximab. We also applied Fisher's exact test (FET) to assess potential associations between drug resistance and the presence of mutations or CNAs. Our pan-drug models outperformed other methods based on the area under the precision-recall curve (AUCPR). Our pathway enrichment analyses revealed LDHB-mediated pyruvate metabolism and FYN-mediated focal adhesion might have pivotal roles in paclitaxel resistance, while PINK1-mediated mitophagy might be critical in 5-FU resistance. In addition to transcriptional activation, FET suggested that CNAs in LDHB and PINK1 may also be associated with resistance to paclitaxel and 5-FU, respectively. Furthermore, enrichment results for paclitaxel and cetuximab indicated shared resistance mechanisms between the two drugs. Importantly, our findings are consistent with prior experimental studies, providing literature-based validation of our results. Overall, our DNN-based TL approach achieved strong predictive performance across PDX & TCGA datasets and enrichment analyses provided valuable biological insights into drug resistance mechanisms.

Humans↗
PubMed1986

Biochemical mechanisms of antibiotic resistance in a clinical isolate of Mycobacterium fortuitum. Presence of beta-lactamase and aminoglycoside-acetyltransferase and possible participation of altered drug transport on the resistance mechanism.

Mycobacterium fortuitum was isolated from specimens of bone marrow from a patient with chronic osteomyelitis. This isolate was resistant to most antimycobacterial drugs, aminoglycosides, and beta-lactam antibiotics. Cell-free extracts from the clinical isolate contained an aminoglycoside acetyltransferase and beta-lactamase. On the basis of substrate specificity, the former enzyme was identified as the acetyltransferase (3), subtype III or IV. However, no positive correlation could be observed between resistance levels (minimal inhibitory concentrations) and the degree of inactivation of aminoglycosides. In vitro, the enzyme reaction required 40 to 60 min to completely inactivate kanamycin. Protein synthesis by ribosomes prepared from this clinical isolate was inhibited by one tenth the concentration of aminoglycosides required to inhibit growth of whole cells. These results suggest that some crypticity factor(s), such as the decreased permeability of drugs, may participate in the intrinsic resistance of the organism.

Acetyltransferases↗
PubMed2004

[Study of resistance mechanism on cefotaxime resistant Proteus mirabilis isolated from clinical specimens and its clinical background].

Over a 6-year period (1997 to 2002), 56 strains of Proteus mirabilis (12% of the total number of P. mirabilis isolates obtained) resistant to ampicillin, piperacillin, cefazolin and cefoperazone by routine antimicrobial testing method, were isolated in Saitama Medical School Hospital. Of the 56 strains resistant to 4 beta-lactams, 12 strains were studied and were found to produce extended-spectrum beta-lactamases, identified as CTX-M-10 group and Toho-1 group in 8 and 2 strains, respectively. Susceptibility testing showed that 12 strains were resistant to cefotaxime, and cepodoxime, and ceftriaxon but susceptible to ceftazidime. Moreover, all of the beta-lactamases were inhibited by clavulanic acid. Of the 12 strains, one strain showed resistance to cephamycins such as cefoxitin, cefmetazole and cefotetan. Four of the twelve patients had infections caused by ESBL producing P. mirabilis, and eight patients were colonized, as confirmed by clinical and laboratory findings. The infections were urinary tract infections (two episodes), pneumonia (one episode), and sepsis (one episode). These patients had a favorable response to antibiotic therapy including cephalosporin. From these findings, CTX-M-type beta-lactamase producing P. mirabilis strains were confirmed from clinical specimens in our hospital.

Cefotaxime↗
PubMed1979

Resistance mechanisms of multiply resistant pneumococci: antibiotic degradation studies.

Strains of Streptococcus pneumoniae resistant to penicillin have been reported from several countries around the world. Many South African isolates, in addition, exhibit resistance to tetracycline, chloramphenicol, erythromycin, clindamycin, and cotrimoxazole in varying patterns. A qualitative test of the ability of antibiotic-resistant pneumococci to inactivate penicillin, oxacillin, cephalothin, cefoxitin, chloramphenicol, tetracycline, minocycline, erythromycin, clindamycin, streptomycin, gentamicin, and cotrimoxazole revealed that only chloramphenicol was degraded. This finding was confirmed in a quantitative test in which the residual antimicrobial activity of broth containing chloramphenicol in subinhibitory concentrations was determined after incubation with antibiotic-resistant bacteria. Chloramphenicol resistance was shown to be associated with the production of inducible chloramphenicol acetyltransferase. No beta-lactamase activity was demonstrated. Plasmid deoxyribonucleic acid was not demonstrable in partially purified lysates of antibiotic-resistant strains of S. pneumoniae.

Acetyltransferases↗
PubMed1997

[Bacterial resistance mechanisms for tetracyclines].

Tetracycline resistance mechanism is unique in bacterial resistance mechanisms because of being mainly based on the drug efflux except for the ribosomal protection mechanism in some tetracycline-resistant Gram-positive bacteria. Tetracycline efflux proteins such as Tet(B) and Tet(C) of Gram-negative bacteria are estimated to have 12-membrane-spanning structure common to the major facilitator family transporters. We experimentally proved the 12-membrane-spanning structure of Tet(B) by site-directed chemical labeling. On the other hand, the tetracycline efflux proteins such as Tet(K) and Tet(L) of Gram-positive bacteria are estimated to have 14-membrane-spanning structure. We first presented the experimental evidence for the 14-spanning structure of Tet(K) based on the Tet(K)-PhoA fusion protein analysis. Another mechanism of tetracycline resistance is a ribosomal protection encoded by tet(M) and let(O). These genes encode the elongation factor(EF-Tu or EF-G)-like protein, whereas the molecular mechanism of the resistance has not yet been revealed.

Antiporters↗