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Multiple drug resistance to antibacterial agents, antifungals, antivirals, antiprotozoals, and antitumor agents has risen spectacularly in the last decade or so and presently threatens eventually to put an end to successful chemotherapy in all of the above fields. This review summarizes the known origins of the problem, its present dimensions, the means employed to combat the phenomenon and promising avenues for future developments.
The multiple drug resistance of neoplastic cells is mediated by overexpression of the human MDR1 gene, which encodes the transmembrane efflux pump P-glycoprotein. In both cell lines and human tumors the MDR phenotype closely correlates with MDR1 mRNA and P-glycoprotein levels. Reversion of the MDR phenotype was attempted in human colorectal adenocarcinoma doxorubicin (Dx)-resistant cells (Lo Vo/Dx) by long-term administration of an equimolecular mixture of three unmodified ODNs (18mer) targeted to adjacent binding sites of the MDR1 mRNA and carried by a synthetic cationic lipid (DOTAP). Three different experimental parameters were used to evaluate the antimessenger agent's effectiveness in comparison with a random sequence ODN: the level of cell resistance to Dx; the level of P-glycoprotein (determined by flow cytometry); the level of MDR1 mRNA (determined by quantitative RT-PCR). Experimental data indicate that the level of both the MDR1 mRNA and the P-glycoprotein is reduced by approximately 50% by treatment of Lo Vo/Dx cells with a 10 microM total concentration of the aODN mixture every 24 h for 15 days. In agreement with these findings, sensitivity to Dx of the antimessenger agent-treated Lo Vo/Dx cells was almost doubled in comparison with random sequence ODN-treated controls.
Multiple drug resistance plasmid NR1 is shown to code for at least 10 low molecular weight RNAs. These species, ranging in size from 60 to 120 nucleotides, have been purified from minicells by two-dimensional gel electrophoresis and characterized by RNase T1 fingerprinting. Hybridization of purified RNAs to restriction endonuclease digests of NR1 DNA indicates that most are derived from the resistance transfer factor region of the plasmid genome. One RNA was found to be coded by the transposable tetracycline resistance element Tn10, and several are associated with DNA fragments that contain origins of replication.
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Breast cancer is a significant health problem in terms of both morbidity and mortality, with approximately 12% of women directly affected by this disease. Chemotherapy, given to patients with earlier stage disease, has a good survival impact and may contribute to cure. The failure of chemotherapeutic drugs to eradicate cancer cells in more advanced disease states may be due to intrinsic or acquired drug resistance, including multiple drug resistance. The drug resistance observed in breast cancer patients is likely to be multifactorial, involving mechanisms such as altered expression and/or activity of drug efflux pumps, nuclear DNA-binding enzymes, metabolizing and conjugating enzymes, and mismatch repair deficiency. More extensive transcriptomic and proteomic analyses of breast tumour and normal biopsies, followed by functional genomic studies in relevant cell line models, should increase our understanding of this phenomenon and lead to therapies being individualized for identifiable subgroups of breast cancer patients.
A study was conducted to ascertain the prevalence of copper resistant Salmonella typhi isolates in south Karnataka. Of the 186 strains studied, 26 (13.97%) were found to be copper resistant. Among the copper resistant strains 19 (73.08%) were found multi drug resistant. All copper resistant strains remained uniformly sensitive to ceftriaxone, ciprofloxacin and norfloxacin. Multiple drug resistance was exclusively associated with E1 phage types.
Of the 173 clinical strains of Vibrio cholerae O139 isolated from India, Bangladesh, and Thailand tested, six strains from India were resistant to tetracycline, ampicillin, chloramphenicol, kanamycin, and gentamicin. These six strains harbored a self-transmissible plasmid that mediated resistance to tetracycline, ampicillin, chloramphenicol, kanamycin, gentamicin, sulfamethoxazole, trimethoprim, and O/129. The multiple drug resistance plasmids were 200 kb in size and belonged to the incompatibility group C. Although a majority of the O139 strains (94.8%) were highly resistant to streptomycin, sulfamethoxazole, trimethoprim, and O/129, the tetracycline-susceptible strains so far tested were plasmid-negative. The data suggest the existence of two distinct multiple antimicrobial agent resistance (MAR) patterns in V. cholerae O139.
Pseudomonas aeruginosa has been regarded as one of the most stubborn pathogens that easily acquire resistance to various antimicrobial agents. Recently, several clinical isolates that have acquired multiple-resistance to carbapenems, fluoroquinolones, and newly developed aminoglycosides such as amikacin have been reported. Thus, the "drug-resistant P. aeruginosa" was designated as a "class 4 pathogen" in the new "Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients with Infections" in Japan. It is generally considered that no medical facility can escape from severe attack by both multiple-drug resistant gram-positive cocci such as MRSA and gram-negative rods including P. aeruginosa in the 21st century. Therefore, emergency countermeasures should be anticipated to prevent further proliferation of these multiple-drug resistant pathogens.
Izaki, Kazuo (University of Tokyo, Tokyo, Japan), Kan Kiuchi, and Kei Arima. Specificity and mechanism of tetracycline resistance in a multiple drug resistant strain of Escherichia coli. J. Bacteriol. 91:628-633. 1966.-A decrease in the uptake of tetracycline occurred concurrently with a rise in the level of resistance of a multiple drug resistant strain of Escherichia coli grown in the presence of tetracycline. Although the strain was also resistant to streptomycin and chloramphenicol, growth in the presence of these two antibiotics did not influence the uptake of tetracycline. The induction of resistance, or decreased uptake of tetracycline, was dependent on growth of the organism in the presence of the drug. Decreased uptake of tetracycline could not be induced in a sensitive strain of the same organism under conditions suitable for induction of the resistant strain. The decrease in accumulating power of the resistant organism cultured in the presence of tetracycline does not appear to be due to selection of a resistant strain from cultures containing both resistant and sensitive strains.
The correlation between rifampin resistance and multiple drug resistance in 236 clinical isolates of Mycobacterium tuberculosis was investigated in this thesis. It has found that 99.4% of the strains with rifampin resistance were multidrug-resistant strains and 89% of the multidrug-resistant strains were resistant to rifampin. This result showed that the rifampin resistance of Tuberculosis baccilli could be used as the marker of multidrug resistance of Mycobacterium tuberculosis.
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A line of Syrian hamster RSV-ransformed fibroblasts having resistance to a number of cytostatics was shown to differ from the parental drug-sensitive line by an extremaly low expression of the integrin alpha v beta 3. In vitro invasive activity of the drug-resistrant cells appeared to be lower than that of their drug-sensitive counterparts. The role of integrin alpha v beta 3 in malignant phenotype and multiple drug resistance of tumor cells is discussed.
We examined the ability of verapamil, a Ca2+ channel blocker, to overcome Vinca alkaloid and multiple drug resistance in our CEM/VLB100 and CEM/DOX human leukemic lymphoblasts. Compared with the parent CCRF-CEM cells, CEM/VLB100 cells are approximately equal to 200- to 800-fold resistant to vinblastine and express cross-resistance to vincristine, doxorubicin, and other "natural product" drugs, as determined by comparing 50% inhibitory concentrations in a 48-h growth inhibition assay. Verapamil (10 microM) decreased the 50% inhibitory concentrations for Vinca alkaloids in CEM/VLB100 cells by approximately equal to 75- to 85-fold but caused only slight (approximately equal to 2- to 5-fold) decreases in 50% inhibitory concentrations for anthracyclines, epipodophyllotoxins, and other tubulin-binding drugs (colchicine and podophyllotoxin). Qualitatively similar results were obtained with doxorubicin-resistant cells, termed CEM/DOX; verapamil caused a 19-fold increase in doxorubicin toxicity but 67- and 3500-fold increases in the toxicities of vinblastine and vincristine, respectively. These results indicate that the effect of verapamil is relatively greater for Vinca alkaloids, with less pronounced effects for the other natural product drugs against which these cells express multiple drug resistance. In flow cytometric studies, individually nontoxic or minimally toxic concentrations of vinblastine plus verapamil caused measurable accumulation in the G2 + M phase as early as 4 h after the drug combination was added to cultures of CEM/VLB100 cells; this finding correlated with a comparable increase in the number of cells in mitosis and measurable decreases in the total number of cells. Since similar effects on cell cycle distribution, percentage of cells in mitosis, and cell number were seen when CEM/VLB100 cells were treated with toxic concentrations of vinblastine alone, we conclude that the primary toxicity of the vinblastine-verapamil combination stems from the alkaloid. Further, the rapid lytic effect of the drug combination was associated with cellular vacuolization. The vacuoles did not stain for lipids, and increases in their number were evident within 2 to 4 h after drug treatment. We suggest that verapamil enhances Vinca alkaloid cytotoxicity by altering "cryptic" cytotoxic targets, possibly related to these vacuoles, through some as yet undefined membrane effect.
Salmonella enterica serovar Typhi (S. typhi) is the aetiological agent of typhoid fever, a serious invasive bacterial disease of humans with an annual global burden of approximately 16 million cases, leading to 600,000 fatalities. Many S. enterica serovars actively invade the mucosal surface of the intestine but are normally contained in healthy individuals by the local immune defence mechanisms. However, S. typhi has evolved the ability to spread to the deeper tissues of humans, including liver, spleen and bone marrow. Here we have sequenced the 4,809,037-base pair (bp) genome of a S. typhi (CT18) that is resistant to multiple drugs, revealing the presence of hundreds of insertions and deletions compared with the Escherichia coli genome, ranging in size from single genes to large islands. Notably, the genome sequence identifies over two hundred pseudogenes, several corresponding to genes that are known to contribute to virulence in Salmonella typhimurium. This genetic degradation may contribute to the human-restricted host range for S. typhi. CT18 harbours a 218,150-bp multiple-drug-resistance incH1 plasmid (pHCM1), and a 106,516-bp cryptic plasmid (pHCM2), which shows recent common ancestry with a virulence plasmid of Yersinia pestis.
A 37-year-old homosexual man began antiretroviral combination therapy with didanosine (ddI), lamivudine (3TC) and indinavir (IDV) after being exposed previously to zidovudine (ZDV), ddI and 3TC in different sequential regimens. The patient's viral load did not fall below a detectable level despite his adherence to drug therapy, which was considered optimal. Stavudine (d4T) was prescribed in the third month of treatment instead of ddI without any evident improvement in the treatment response. A point mutation nested PCR assay showed that the patient carried a virus with a codon Q151M mutation, which confers multiple drug resistance to nucleoside analogues. Genetic sequence analysis showed that, despite none of the classically associated mutations to Q151M being present at the beginning of treatment, continuous genetic evolution under selective drug pressure allowed the virus to accumulate mutations at codons 62, 74 and 116 over time. As expected, the CD4+ cell count declined during the study period, and the viral load remained detectable.
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Sulfadoxine-pyrimethamine-resistant and chloroquine resistant, but mefloquine sensitive (MIC 5 x 10(-9] isolates of Plasmodium falciparum were used to study the emergence of mefloquine resistance. The continuously cultured isolates which were exposed intermittantly to varying concentrations of mefloquine alone became insensitive to the drug at 1 x 10(-7) M after 12 months, whereas the culture line exposed to the combination of mefloquine, sulfadoxine and pyrimethamine became only slightly insensitive to mefloquine (MIC 2 x 10(-8]. Thus, the efficacy of mefloquine may be prolonged through use in combination with sulfadoxine-pyrimethamine.
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was collected from children with bullous impetigo in 2003 and 2004. One strain collected in 2003 was Panton-Valentine leucocidin (PVL) positive. In 2004, a multiple-drug-resistant PVL(+) CA-MRSA strain was isolated from an athlete with a cutaneous abscess. These strains were analyzed by multilocus sequence typing, spa typing, agr typing, coagulase typing, staphylococcal cassette chromosome mec (SCCmec) typing, PCR assay for 30 virulence genes, drug susceptibility testing, pulsed-field gel electrophoresis, and for plasmids. The two Japanese PVL(+) CA-MRSA strains belonged to the globally extant ("pandemic") sequence type 30 (ST30) with SCCmec IV. A transmissible, multiple-drug resistance plasmid emerged in such ST30 strains. The PVL(-) CA-MRSA strains ("domestic" CA-MRSA) accumulated for bullous impetigo, exhibiting new genotypes. Hospital-acquired MRSA of ST91 (but not pandemic ST5) shared common features with the PVL(-) CA-MRSA strain.