Loading...
10 results
Search Results
Now showing 1 - 10 of 10
- Are Virulence and Antibiotic Resistance Genes Linked? A Comprehensive Analysis of Bacterial Chromosomes and PlasmidsPublication . Darmancier, Helena; Domingues, Célia P. F.; Rebelo, João S.; Amaro, Ana; Dionisio, Francisco; Pothier, Joel; Serra, Octavio; Nogueira, TeresaAlthough pathogenic bacteria are the targets of antibiotics, these drugs also affect hundreds of commensal or mutualistic species. Moreover, the use of antibiotics is not only restricted to the treatment of infections but is also largely applied in agriculture and in prophylaxis. During this work, we tested the hypothesis that there is a correlation between the number and the genomic location of antibiotic resistance (AR) genes and virulence factor (VF) genes. We performed a comprehensive study of 16,632 reference bacterial genomes in which we identified and counted all orthologues of AR and VF genes in each of the locations: chromosomes, plasmids, or in both locations of the same genome. We found that, on a global scale, no correlation emerges. However, some categories of AR and VF genes co-occur preferentially, and in the mobilome, which supports the hypothesis that some bacterial pathogens are under selective pressure to be resistant to specific antibiotics, a fact that can jeopardize antimicrobial therapy for some human-threatening diseases
- The power of dying slowly - persistence as unintentional dormancyPublication . Rebelo, João S.; Domingues, Célia P. F.; Monteiro, Francisca; Nogueira, Teresa; Dionisio, FranciscoPersistence is a state of bacterial dormancy where cells with low metabolic activity and growth rates are phenotypically tolerant to antibiotics and other cytotoxic substances. Given its obvious advantage to bacteria, several researchers have been looking for the genetic mechanism behind persistence. However, other authors argue that there is no such mechanism and that persistence results from inadvertent cell errors. In this case, the persistent population should decay according to a power-law with a particular exponent of −2. Studying persisters’ decay is, therefore, a valuable way to understand persistence. Here we simulated the fate of susceptible cells in laboratory experiments in the context of indirect resistance. Eventually, under indirect resistance, detoxifying drug-resistant cells save the persister cells that leave the dormant state and resume growth. The simulations presented here show that, by assuming a power-law decline, the exponent is close to −2, which is the expected value if persistence results from unintentional errors. Whether persisters are cells in a moribund state or, on the contrary, result from a genetic program, should impact the research of anti-persistent drugs.
- Harmful behaviour through plasmid transfer: a successful evolutionary strategy of bacteria harbouring conjugative plasmidsPublication . Domingues, Célia P. F.; Rebelo, João S.; Monteiro, Francisca; Nogueira, Teresa; Dionisio, FranciscoConjugative plasmids are extrachromosomal mobile genetic elements pervasive among bacteria. Plasmids' acquisition often lowers cells' growth rate, so their ubiquity has been a matter of debate. Chromosomes occasionally mutate, rendering plasmids cost-free. However, these compensatory mutations typically take hundreds of generations to appear after plasmid arrival. By then, it could be too late to compete with fast-growing plasmid-free cells successfully. Moreover, arriving plasmids would have to wait hundreds of generations for compensatory mutations to appear in the chromosome of their new host. We hypothesize that plasmid-donor cells may use the plasmid as a ‘weapon’ to compete with plasmid-free cells, particularly in structured environments. Cells already adapted to plasmids may increase their inclusive fitness through plasmid transfer to impose a cost to nearby plasmid-free cells and increase the replication opportunities of nearby relatives. A mathematical model suggests conditions under which the proposed hypothesis works, and computer simulations tested the long-term plasmid maintenance. Our hypothesis explains the maintenance of conjugative plasmids not coding for beneficial genes. This article is part of the theme issue ‘The secret lives of microbial mobile genetic elements’.
- The Impact of Non-Pathogenic Bacteria on the Spread of Virulence and Resistance GenesPublication . Dionisio, Francisco; Domingues, Célia P. F.; Rebelo, João S.; Monteiro, Francisca; Nogueira, TeresaThis review discusses the fate of antimicrobial resistance and virulence genes frequently present among microbiomes. A central concept in epidemiology is the mean number of hosts colonized by one infected host in a population of susceptible hosts: R0. It characterizes the disease’s epidemic potential because the pathogen continues its propagation through susceptible hosts if it is above one. R0 is proportional to the average duration of infections, but non-pathogenic microorganisms do not cause host death, and hosts do not need to be rid of them. Therefore, commensal bacteria may colonize hosts for prolonged periods, including those harboring drug resistance or even a few virulence genes. Thus, their R0 is likely to be (much) greater than one, with peculiar consequences for the spread of virulence and resistance genes. For example, computer models that simulate the spread of these genes have shown that their diversities should correlate positively throughout microbiomes. Bioinformatics analysis with real data corroborates this expectation. Those simulations also anticipate that, contrary to the common wisdom, human’s microbiomes with a higher diversity of both gene types are the ones that took antibiotics longer ago rather than recently. Here, we discuss the mechanisms and robustness behind these predictions and other public health consequences.
- The Perfect Condition for the Rising of Superbugs: Person-to-Person Contact and Antibiotic Use Are the Key Factors Responsible for the Positive Correlation between Antibiotic Resistance Gene Diversity and Virulence Gene Diversity in Human MetagenomesPublication . Domingues, Célia P. F.; Rebelo, João S.; Pothier, Joel; Monteiro, Francisca; Nogueira, Teresa; Dionisio, FranciscoHuman metagenomes with a high diversity of virulence genes tend to have a high diversity of antibiotic-resistance genes and vice-versa. To understand this positive correlation, we simulated the transfer of these genes and bacterial pathogens in a community of interacting people that take antibiotics when infected by pathogens. Simulations show that people with higher diversity of virulence and resistance genes took antibiotics long ago, not recently. On the other extreme, we find people with low diversity of both gene types because they took antibiotics recently—while antibiotics select specific resistance genes, they also decrease gene diversity by eliminating bacteria. In general, the diversity of virulence and resistance genes becomes positively correlated whenever the transmission probability between people is higher than the probability of losing resistance genes. The positive correlation holds even under changes of several variables, such as the relative or total diversity of virulence and resistance genes, the contamination probability between individuals, the loss rate of resistance genes, or the social network type. Because the loss rate of resistance genes may be shallow, we conclude that the transmission between people and antibiotic usage are the leading causes for the positive correlation between virulence and antibiotic-resistance genes.
- Multi-Drug Resistance in Bacterial Genomes—A Comprehensive Bioinformatic AnalysisPublication . Domingues, Célia P. F.; Rebelo, João S.; Dionisio, Francisco; Nogueira, TeresaAntimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug resistance considering the ResFinder antimicrobial classes. We found that more than 95% of the genomes harbor genes associated with resistance to disinfectants, glycopeptides, macrolides, and tetracyclines. On average, each genome encodes resistance to more than nine different classes of antimicrobial drugs. We found higher-than-expected co-occurrences of resistance genes in both plasmids and chromosomes for several classes of antibiotic resistance, including classes categorized as critical according to the World Health Organization (WHO). As a result of antibiotic-resistant priority pathogens, higher-than-expected co-occurrences appear in plasmids, increasing the potential for resistance dissemination. For the first time, co-occurrences of antibiotic resistance have been investigated for priority pathogens as defined by the WHO. For critically important pathogens, co-occurrences appear in plasmids, not in chromosomes, suggesting that the resistances may be epidemic and probably recent. These results hint at the need for new approaches to treating infections caused by critically important bacteria.
- What Is the Impact of Antibiotic Resistance Determinants on the Bacterial Death Rate?Publication . Luz, Bruno T. S.; Rebelo, João S.; Monteiro, Francisca; Dionisio, FranciscoObjectives: Antibiotic-resistant bacteria are widespread, with resistance arising from chromosomal mutations and resistance genes located in the chromosome or in mobile genetic elements. While resistance determinants often reduce bacterial growth rates, their influence on bacterial death under bactericidal antibiotics remains poorly understood. When bacteria are exposed to bactericidal antibiotics to which they are susceptible, they typically undergo a two-phase decline: a fast initial exponentially decaying phase, followed by a persistent slow-decaying phase. This study examined how resistance determinants affect death rates during both phases. Methods: We analyzed the death rates of ampicillin-exposed Escherichia coli populations of strains sensitive to ampicillin but resistant to nalidixic acid, rifampicin, or both, and bacteria carrying the conjugative plasmids RN3 or R702. Results: Single mutants resistant to nalidixic acid or rifampicin decayed faster than sensitive cells during the early phase, whereas the double-resistant mutant exhibited prolonged survival. These contrasting impacts suggest epistatic interactions between both chromosomal mutations. Persistent-phase death rates for chromosomal mutants did not differ significantly from wild-type cells. In contrast, plasmid-carrying bacteria displayed distinct dynamics: R702 plasmid-bearing cells showed higher persistent-phase death rates than plasmid-free cells, while RN3 plasmid-bearing cells exhibited lower rates. Conclusions: Bactericidal antibiotics may kill bacteria resistant to other antibiotics more effectively than wild-type cells. Moreover, epistasis may occur when different resistance determinants occur in the same cell, impacting the bactericidal potential of the antibiotic of choice. These results have significant implications for optimizing bacterial eradication protocols in clinical settings, as well as in animal health and industrial food safety management.
- The perfect condition for the rising of superbugs: person-to-person contagion and antibiotic use are the key factors responsible for the positive correlation between antibiotic resistance gene diversity and virulence gene diversity in human metagenomesPublication . Domingues, Célia P. F.; Rebelo, João S.; Nogueira, Teresa; Pothier, Joel; Monteiro, Francisca; Dionisio, FranciscoThis study aims to understand the cause of the recent observation that humans with a higher diversity of virulence genes in their metagenomes tend to be precisely those with higher diversity of antibiotic-resistance genes. We simulated the transferring of virulence and antibiotic-resistance genes in a community of interacting people where some take antibiotics. The diversities of the two genes types became positively correlated whenever the contagion probability between two people was higher than the probability of losing resistant genes. However, no such positive correlations arise if no one takes antibiotics. This finding holds even under changes of several simulations’ parameters, such as the relative or total diversity of virulence and resistance genes, the contagion probability between individuals, the loss rate of resistance genes, or the social network type. Because the loss rate of resistance genes may be shallow, we conclude that the contagion between people and antibiotic usage is the leading cause of establishing the positive correlation mentioned above. Therefore, antibiotic use and something as prosaic as the contagion between people may facilitate the emergence of virulent and multi-resistant bacteria in people’s metagenomes with a high diversity of both gene types. These superbugs may then circulate in the community.
- COVID-19 lockdowns may reduce resistance genes diversity in the human microbiome and the need for antibioticsPublication . Rebelo, João S.; Domingues, Célia P. F.; Dionisio, Francisco; Gomes, Manuel C.; Botelho, Ana; Nogueira, TeresaRecently, much attention has been paid to the COVID-19 pandemic, yet bacterial resistance to antibiotics remains a serious and unsolved public health problem, which kills thousands of people annually, being an insidious and silent pandemic. In this study, we explored the idea of confinement and the tightening of the hygiene measures to contain the spreading of coronavirus, to simulate the effect that it has on lowering the spreading of pathogenic bacteria in a human network, and on the need to use antibiotics. For that, we used computational biology to generate simulations
- Plasmids Increase the Competitive Ability of Plasmid-Bearing Cells Even When Transconjugants Are Poor Donors, as Shown by Computer SimulationsPublication . Rebelo, João S.; Domingues, Célia P. F.; Nogueira, Teresa; Dionisio, FranciscoBacterial cells often suffer a fitness cost after conjugative plasmids’ entry because these cells replicate slower than plasmid-free cells. Compensatory mutations may appear after tens of or a few hundred generations, reducing or eliminating this cost. A previous work based on a mathematical model and computer simulations has shown that plasmid-bearing cells already adapted to the plasmid may gain a fitness advantage when plasmids transfer into neighboring plasmid-free cells because these cells are still unadapted to the plasmid. These slow-growing transconjugants use fewer resources, which can benefit donor cells. However, opportunities for compensatory mutations in transconjugants increase if these cells become numerous (through replication or conjugation). Moreover, transconjugants also gain an advantage when transferring the plasmid, but the original donors may be too distant from conjugation events to gain an advantage. To understand which consequence prevails, we performed further computer simulations allowing versus banning transfer from transconjugants. The advantage to donors is higher if transconjugants do not transfer plasmids, mainly when donors are rare and when the plasmid transfer rate (from donors) is high. These results show that conjugative plasmids are efficient biological weapons even if the transconjugant cells are poor plasmid donors. After some time, conjugative plasmids gain other host-benefit genes, such as virulence and drug-resistance.