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At least 433 records · Page 24Linked to original sources
PubMed2001

In vitro evolution of the human immunodeficiency virus type 1 gag-protease region and maintenance of reverse transcriptase resistance following prolonged drug exposure.

We studied the human immunodeficiency virus type 1 phenotypic and genotypic profiles of a dual drug-resistant isolate (isolate 14aPost-DR) selected for zidovudine (ZDV) and lamivudine (3TC) resistance and then cultured in the presence of 3TC and a protease inhibitor: indinavir (IDV), ritonavir, or KNI-272. The IDV-treated virus was highly resistant to 3TC, ZDV, and IDV and accumulated protease mutations at positions M46I and V82F. A change from alanine to valine was observed in 4 of 10 clones in the P2 position of the p7-p1 Gag-protease cleavage site, linked to position M46I in the dominant viral quasispecies. Previous 3TC resistance did not impair the development of additional mutations in the protease and Gag-protease cleavage regions.

Drug Resistance, Microbial↗
PubMed1978

Microbial transformations of styrene and [14C] styrene in soil and enrichment cultures.

Two different mechanisms were responsible for the disappearance of styrene in enrichment cultures: (i) a mixed population of microorganisms, capable of utilizing styrene as a sole carbon source, oxidized this substrate to phenylethanol and phenylacetic acid; (ii) the culture also mediated polymerization of the monomer to low-molecular-weight styrene oligomers. This chemical reaction probably occurred as the result of microbial degradation of butylcatechol, an antioxidant polymerization inhibitor present in commercial styrene. The resultant polymer material was subsequently metabolized. In soil incubation studies, 14CO2 evolution from applied [8-14C] styrene was used to estimate microbial degradation. Approximately 90 percent of the labeled carbon was evolved from a 0.2 percent addition, and about 75 percent was lost from the 0.5 percent application over a 16-week period.

Bacteria↗
PubMed1998

Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria.

The available genomic sequences of three pathogenic and three nonpathogenic bacteria were analyzed to identify known and putative drug-specific and multidrug resistance transport systems. Escherichia coli was found to encode 29 such pumps, and with the exception of the archaebacterium Methanococcus jannaschii, the numbers of multidrug efflux pumps encoded within genomes of the other organisms were found to be approximately proportional to their total numbers of encoded transport systems as well as to total genome size. The similar numbers of chromosomally encoded multidrug efflux systems in pathogens and nonpathogens suggests that these transporters have not arisen recently in pathogens in response to antimicrobial chemotherapy. Phylogenetic analyses of the four transporter families that contain drug efflux permeases indicate that drug resistance arose rarely during the evolution of each family and that the diversity of current drug efflux pumps within each family arose from just one or a very few primordial systems. However, although the ability to confer drug efflux appears to have emerged on only a few occasions in evolutionary time and was stably maintained as an evolutionary trait, modulation of the substrate specificities of these systems has occurred repeatedly. A speculative model is presented that may explain the apparent capability of these multidrug transport systems to mediate drug transport from the cytoplasm or directly from the phospholipid bilayer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Importance of integrons in the diffusion of resistance.

Horizontal transfer of resistance genes is a successful mechanism for the transmission and dissemination of multiple drug resistance among bacterial pathogens. The impact of horizontally transmitted genetic determinants in the evolution of resistance is particularly evident when resistance genes are physically associated in clusters and transferred en bloc to the recipient cell. Recent advances in the molecular characterisation of antibiotic resistance mechanisms have highlighted the existence of genetic structures. called integrons, involved in the acquisition of resistance genes. These DNA elements have frequently been reported in multi-drug resistant strains isolated from animals and humans, and are located either on the bacterial chromosome or on broad-host-range plasmids. The role of integrons in the development of multiple resistance relies on their unique capacity to cluster and express drug resistance genes. Moreover, the spread of resistance genes among different replicons and their exchange between plasmid and bacterial chromosome are facilitated by the integration of integrons into transposable elements. The association of a highly efficient gene capture and expression system, together with the capacity for vertical and horizontal transmission of resistance genes represents a powerful weapon used by bacteria to combat the assault of antibiotics.

Animal Diseases↗
PubMed1999

Emergence and genetic evolution of HIV-1 variants with mutations conferring resistance to multiple reverse transcriptase and protease inhibitors.

The emergence of genotypic resistance in protease and reverse transcriptase (RT) gene regions was longitudinally evaluated in plasma samples from a group of 12 HIV-1-infected patients treated with different combination of antiretroviral therapies and selected on the basis of their clinical failure. Complex mutational patterns in the reverse transcriptase gene were observed. In particular, combinations of AZT (41L, 67N, 70R, 210W, and 219Q/E) and 3TC (184M) were seen in 10 patients. Two patients presented codon 151 multinucleoside analogue resistance (MNR). Additionally, seven patients harbored RT nonnucleoside analogue-related resistance substitutions (98G, 103N, and 181C). Multiple protease-selected mutations were found in each patient with an average of six substitutions per patient, with 10I/F/V, 63P, 71V, 82A/T, 84V, and 90M being the most prevalent substitutions. Overall, these results showed that for most patients virological failure was coupled with detectable genotypic resistance. Furthermore, most patients exhibited genotypic resistance to almost all available anti-HIV-1 drugs. The high viral loads found in most patients at the end of the study suggest that the replication of these multidrug resistant viruses are not severely compromised. Phylogenetic analysis of these pol sequences revealed that a specific HIV-1 genotype prone to develop multidrug resistance was not found.

Adult↗
PubMed2001

Selection by AZT and rapid replacement in the absence of drugs of HIV type 1 resistant to multiple nucleoside analogs.

We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness.

Amino Acid Sequence↗
PubMed2001

Phylogeny of multidrug transporters.

We currently recognize five large ubiquitous superfamilies and one small eukaryotic-specific family in which cellular multidrug efflux pumps occur. One, the ABC superfamily, includes members that use ATP hydrolysis to drive drug efflux, but the MFS, RND, MATE and DMT superfamilies include members that are secondary carriers, functioning by drug:H(+)or drug:Na(+)antiport mechanisms. The small MET family seems to be restricted to endosomal membranes of eukaryotes, and only a single such system has been functionally characterized. In this review article, these families of drug transporters are discussed and evaluated from phylogenetic standpoints.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Neo-self antigens and the expansion of B-1 cells: lessons from atherosclerosis-prone mice.

The pathogenesis of atherosclerosis involves an inflammatory process that is modulated by the immune system, and within these complex responses we have discerned a possible role for an archetypic B-1 clone. We speculate that due to their immunogenicity and in vivo distribution the "neo"-self determinants created in oxidatively modified LDL are highly stimulatory for certain B-1 cell clones. These neo-self determinants, which can be created chemically, by somatic processes, may in fact represent the molecular analogues of somatic maturation, or even aging. These changes, including those on non-protein antigens induced by oxidative metabolism, amongst others, create neo-determinants against which the host no doubt can not develop rigorous B-cell tolerance. The onset of expression of these oxidative neo-determinants relatively late in development may well serve a useful function for the highly evolved mammalian immune system, as targeting by evolutionarily selected B-1 clones may facilitate the amplification of other useful antibody-mediated physiologic functions. As in the case of the T15 clone, these antibodies may aid in protection against common microbial pathogens. Hence we postulate that during the evolution of the adaptive immune system the neo-self antigenic milieu may have been exploited for the natural selection of primordial clonal specificities. The T15 B-1 clone may then illustrate a common paradigm in which there has been natural selection based on utility for the defense of the individual from environmental threats, as well as for possible "housekeeping" role(s) and the maintenance of cellular homeostasis.

Animals↗
PubMed1994

Dictyostelium discoideum, a lower eukaryote model for the study of DNA repair: implications for the role of DNA-damaging chemicals in the evolution of repair proficient cells.

The evolution of the ability of living cells to cope with stress is crucial for the maintenance of their genetic integrity. Yet low levels of mutation must remain to allow adaptation to environmental changes. The cellular slime mold D. discoideum is a good system for studying molecular aspects of the repair of lethal and mutagenic damage to DNA by radiation and chemicals. The wild-type strains of this soil microorganism are extremely resistant to DNA damaging agents. In nature the amoeboid cells in their replicative stage feed on soil bacteria and are exposed to numerous DNA-damaging chemicals produced by various soil microorganisms. It is probable that the evolution of repair systems in this organism and perhaps in others is a consequence of the necessity to cope with chemical damage which also confers resistance to radiation.

Animals↗
PubMed2004

Evolutionary dynamics of invasion and escape.

Whenever life wants to invade a new habitat or escape from a lethal selection pressure, some mutations may be necessary to yield sustainable replication. We imagine situations like (i) a parasite infecting a new host, (ii) a species trying to invade a new ecological niche, (iii) cancer cells escaping from chemotherapy, (iv) viruses or microbes evading anti-microbial therapy, and also (v) the repeated attempts of combinatorial chemistry in the very beginning of life to produce self-replicating molecules. All such seemingly unrelated situations have a common structure in terms of Darwinian dynamics: a replicator with a basic reproductive ratio less than one attempts to find some mutations that allow indefinite survival. We develop a general theory, based on multitype branching processes, to describe the evolutionary dynamics of invasion and escape.

Animals↗
PubMed2002

Intraspecific variation in the 16S rRNA gene sequences of Mycoplasma agalactiae and Mycoplasma bovis strains.

Intraspecific variation in the 16S rRNA genes of 17 Mycoplasma agalactiae and eight Mycoplasma bovis isolates was investigated to determine the degree of sequence variation in these two species and to determine whether the polymorphisms in the 16S rRNA genes could be used for the construction of an evolutionary tree and as epidemiological markers. A high degree of variation was found within isolates (between operons) and between isolates of both species. In contrast to M. capripneumoniae no distinct evolutionary pattern could be seen, probably because there are functional systems for gene conversion in M. agalactiae and M. bovis. However, the non-European isolates of M. agalactiae shared three characteristic nucleotides and European isolates from the same or neighbouring countries were very similar. Differences within isolates included both polymorphic positions and sequence length differences between operons. The amount of variation within isolates of the respective species ranged from zero to seven polymorphisms for M. agalactiae and from zero to four polymorphisms for M. bovis. The high degree of variation suggests the potential for misdiagnosis of species in diagnostic PCR assays based on the 16S rRNA gene sequences. All isolates of both species had a thymidine in position 912 (E. coli numbering) that causes streptomycin resistance in several bacterial species and which is characteristic for the members of the hominis group. As expected, when five M. agalactiae and three M. bovis isolates were tested for streptomycin susceptibility, they all demonstrated streptomycin resistance. M. agalactiae and M. bovis were found to have high intraspecific variation in their 16S rRNA gene and the polymorphisms patterns indicate that gene conversion takes place.

Animals↗
PubMed2001

Antibiotic resistance in the absence of selective pressure.

Antibiotic resistance poses a serious threat to modern medical practice making treatment more difficult and is associated with increased mortality among patients infected with resistant organisms. There is clear evidence that acquisition of resistance is associated with a decrease in the fitness of the organisms at least in the short term. Evidence from in vitro experiments indicates that bacteria have the ability to adapt to this deficit and recover fitness on serial passage. More recent results show that identical organisms isolated from patients in outbreaks have an initial deficit but that adaptation occurs in vivo. Strategies directed towards controlling resistance must move beyond wishful thinking that supposes that these organisms will disappear merely with control of prescribing. In some cases, resistance will not disappear because there is no evolutionary disadvantage in being resistant once adaptation has taken place. It is important, therefore, that we direct our efforts towards preventing primary resistance emerging and in limiting the spread of resistant strains. Ultimately, we must look again to new drug discovery to improve our therapeutic armoury.

Adaptation, Physiological↗
PubMed2000

The effect of a commercial starter culture addition on the ripening of an artisanal goat's cheese (Cameros cheese).

The evolution of physicochemical parameters, and the most important microbial groups, were determined for the following three batches of 'Cameros' goat's milk cheese during ripening: Batch R elaborated with raw milk, Batch RS elaborated with raw milk and with the addition of a starter culture, and Batch PS elaborated with pasteurized milk and with the addition of the same culture. No differences in total solids (TS) or in the content of NaCl, fat and total nitrogen (expressed as percentages of TS) were found during the ripening. The pH, fat acidity and non-protein nitrogen (NPN, expressed as a percentage of TN) showed significant differences between the batches. The inoculated batches showed the fastest drop in pH at the beginning of the ripening period, but the cheeses of Batch R showed a higher degree of lipolysis and proteolysis. The addition of a starter influenced the microbiological quality of the cheeses. Differences in the counts of Enterobacteriaceae and faecal coliforms were found between Batches R and RS after 15 days. Staphylococcus aureus increased in number during the early period of ripening and attained a population above 6 log cfu g-1 in Batch R in the period from 5 to 10 days. However, enterotoxins were not detected in this Batch. Batch R showed lower values of lactic acid bacteria at the beginning of the ripening period, but no significant differences were found between batches in the period from 5 to 15 days of ripening. At the beginning of the ripening, Lactococcus was the main lactic acid bacteria, with L. lactis lactis being predominant. After 15 days, the lactic acid bacteria counts decreased in the three batches, especially in the cheeses of Batch PS (only 2.2 log cfu g-1 was found at 60 days), as lactococci (the only lactic acid bacteria present in Batch PS) are incapable of growing under the conditions found in cheeses at the end of their ripening period. At this time, Lactobacillus was the predominant genus in Batches R and RS, with L. plantarum predominant. No lactococci were found from day 30 in Batch R and from day 40 in Batch RS. The cheeses of Batch RS received the most favourable scores from the tasting panel for all attributes judged: cut appearance, colour, aroma, taste, texture and general acceptance.

Animals↗