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opencc-zeroJul 2020View details →

Data and code for: Stochastic bacterial population dynamics restrict the establishment of antibiotic resistance from single cells

This dataset contains experimental data and custom R code for likelihood-based model-fitting associated with the manuscript "Stochastic bacterial population dynamics restrict the establishment of antibiotic resistance from single cells". In particular, we estimate the per-cell establishment probability (i.e. probability that a single cell gives rise to a large population) of a resistant strain, in the presence of antibiotics at concentrations below its standard minimum inhibitory concentration. The experiments are conducted here with Pseudomonas aeruginosa, while the model and methods can be applied more generally.

opencc-zeroAug 2020View details →

Dysbiosis individualizes fitness effect of antibiotic resistance in the mammalian gut

The fitness cost of antibiotic resistance in the absence of antibiotics is crucial to the success of suspending antibiotics as a strategy to lower resistance. Here we show that after antibiotic treatment the cost of resistance within the complex ecosystem of the mammalian gut is personalized. Using mice as an in vivo model, we find that the fitness effect of the same resistant mutation can be deleterious in a host, but neutral or even beneficial in other hosts. Such antagonistic pleiotropy is shaped by the microbiota, as in germ-free mice resistance is consistently costly across all hosts and in hosts with similar microbiotas the host specific effect of resistance is reduced. An eco-evolutionary model of competition for resources identifies a general mechanism underlying between host variation and predicts that the dynamics of compensatory evolution of resistant bacteria should be host specific, a prediction that was supported by experimental evolution in vivo. The microbiome of each human is close to unique and our results suggest that the short-term costs of resistance and its long-term within-host evolution will also be highly personalized, a finding that may contribute to the observed variable outcome of withdrawing antibiotics to reduce resistance levels.

opencc-zeroMay 2020View details →

An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen

Therapeutic antibiotic use drives the spread of antibiotic resistance, a major threat to public health. Ideally, clinicians could treat infections with antibiotics without fueling transmission of resistant pathogens. Here, we show proof of concept for an adjunctive therapy approach that allows treatment of target pathogens without the emergence and onward transmission of resistance. Like many of the bacterial species responsible for the antimicrobial resistance crisis, vancomycin-resistant Enterococcus (VRE) is a colonizing opportunistic pathogen and an important cause of drug-resistant healthcare-associated infections. VRE causes life-threatening infections in the bloodstream, but spreads via fecal-oral transmission because it asymptomatically colonizes the gastrointestinal (GI) tract. Thus, there is a physical separation between the VRE targeted by treatment (those in the blood) and the VRE contributing to onward transmission (those in the GI tract). An oral adjuvant that could eliminate or inactivate antibiotic in the GI tract would make possible intravenous patient treatment without promoting transmissible resistance. We tested this idea in a mouse model of VRE GI tract colonization using cholestyramine, which we show binds daptomycin, one of the few remaining front-line antibiotics against VRE. Adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant VRE by up to 80-fold in mice treated with daptomycin. These results provide proof-of-concept for an approach that could reduce the spread of antibiotic resistance for many important hospital pathogens.

opencc-zeroOct 2020View details →

Unique mode of cell division by the mycobacterial genetic resister clones emerging de novo from the antibiotic surviving population

Live cell and timelapse microscopic images of the cells taken from different time points post antibiotic (Rifampicin and Moxifloxacin) exposure. The cells post antibiotic exposure, during their regrowth, showed multiple constriction to divide and generate sister antibiotic resister daughter cells with abrupt increased cell number within less division time by multiple septation. The phenomena of multiple septation can be seen in Miscellaneous Figures (MF. 1-4) and Miscellaneous Movies (MF. 1-4).

opencc-zeroDec 2020View details →

Data from: Fitness benefits to bacteria of carrying prophages and prophage-encoded antibiotic-resistance genes peak in different environments

Understanding the role of horizontal gene transfer (HGT) in adaptation is a key challenge in evolutionary biology. In microbes, an important mechanism of HGT is prophage acquisition (phage genomes integrated into bacterial chromosomes). Prophages can influence bacterial fitness via transfer of beneficial genes (including antibiotic-resistance genes, ARGs), protection from superinfecting phages, or switching to a lytic lifecycle which releases free phages infectious to competitors. We expect these effects to depend on environmental conditions because of, for example, environment-dependent induction of the lytic lifecycle. However, it remains unclear how costs/benefits of prophages vary across environments. Here, studying prophages with/without ARGs in Escherichia coli, we disentangled effects of prophages alone and adaptive genes they carry. In competition with prophage-free strains, benefits from prophages and ARGs peaked in different environments. Prophages were most beneficial when induction of the lytic lifecycle was common, whereas ARGs were more beneficial upon antibiotic exposure and with reduced prophage induction. Acquisition of prophage-encoded ARGs by competing strains was most common when prophage induction, and therefore free phages, were common. Thus, selection on prophages and adaptive genes they carry varies independently across environments, which is important for predicting the spread of mobile/integrating genetic elements and their role in evolution

opencc-zeroJan 2021View details →

Evolution of honey resistance in experimental populations of bacteria depends on the type of honey, and has no major side effects for antibiotic susceptibility

With rising antibiotic resistance, alternative treatments for communicable diseases are increasingly relevant. One possible alternative for some types of infections is honey, used in wound care since before 2000 BCE and more recently in licensed, medical-grade products. However, it is unclear whether medical application of honey results in the evolution of bacterial honey resistance, and whether this has collateral effects on other bacterial traits such as antibiotic resistance. Here, we used single-step screening assays and serial transfer at increasing concentrations to isolate honey-resistant mutants of Escherichia coli. We only detected bacteria with consistently increased resistance to the honey they evolved in with two of the four tested honey products, and the observed increases were small (maximum two-fold increase in IC90). Genomic sequencing and experiments with single-gene knockouts showed a key mechanism by which bacteria increased their honey resistance was by mutating genes involved in detoxifying methylglyoxal, which contributes to the antibacterial activity of Leptospermum honeys. Crucially, we found no evidence that honey adaptation conferred cross-resistance or collateral sensitivity against nine antibiotics from six different classes. These results reveal constraints on bacterial adaptation to different types of honey, improving our ability to predict downstream consequences of wider honey application in medicine.

opencc-zeroDec 2016View details →

Data from: Aquatic animals promote antibiotic resistance gene dissemination in water via conjugation: role of different regions within the zebra fish intestinal tract, and impact on fish intestinal microbiota

The aqueous environment is one of many reservoirs of antibiotic resistance genes (ARGs). Fish, as important aquatic animals which possess ideal intestinal niches for bacteria to grow and multiply, may ingest antibiotic resistance bacteria from aqueous environment. The fish gut would be a suitable environment for conjugal gene transfer including those encoding antibiotic resistance. However, little is known in relation to the impact of ingested ARGs or antibiotic resistance bacteria (ARB) on gut microbiota. Here, we applied the cultivation method, qPCR, nuclear molecular genetic marker and 16S rDNA amplicon sequencing technologies to develop a plasmid-mediated ARG transfer model of zebrafish. Furthermore, we aimed to investigate the dissemination of ARGs in microbial communities of zebrafish guts after donors carrying self-transferring plasmids that encode ARGs were introduced in aquaria. On average, 15% of faecal bacteria obtained ARGs through RP4-mediated conjugal transfer. The hindgut was the most important intestinal region supporting ARG dissemination, with concentrations of donor and transconjugant cells almost 25 times higher than those of other intestinal segments. Furthermore, in the hindgut where conjugal transfer occurred most actively, there was remarkable upregulation of the mRNA expression of the RP4 plasmid regulatory genes, trbBp and trfAp. Exogenous bacteria seem to alter bacterial communities by increasing Escherichia and Bacteroides species, while decreasing Aeromonas compared with control groups. We identified the composition of transconjugants and abundance of both cultivable and uncultivable bacteria (the latter accounted for 90.4%–97.2% of total transconjugants). Our study suggests that aquatic animal guts contribute to the spread of ARGs in water environments.

opencc-zeroDec 2016View details →

Data from: Exposure to dairy manure leads to greater antibiotic resistance and increased mass-specific respiration in soil microbial communities

Intensifying livestock production to meet the demands of a growing global population coincides with increases in both the administration of veterinary antibiotics and manure inputs to soils. These trends have the potential to increase antibiotic resistance in soil microbial communities. The effect of maintaining increased antibiotic resistance on soil microbial communities and the ecosystem processes they regulate is unknown. We compare soil microbial communities from paired reference and dairy manure-exposed sites across the USA. Given that manure exposure has been shown to elicit increased antibiotic resistance in soil microbial communities, we expect that manure-exposed sites will exhibit (i) compositionally different soil microbial communities, with shifts toward taxa known to exhibit resistance; (ii) greater abundance of antibiotic resistance genes; and (iii) corresponding maintenance of antibiotic resistance would lead to decreased microbial efficiency. We found that bacterial and fungal communities differed between reference and manure-exposed sites. Additionally, the β-lactam resistance gene ampC was 5.2-fold greater under manure exposure, potentially due to the use of cephalosporin antibiotics in dairy herds. Finally, ampC abundance was positively correlated with indicators of microbial stress, and microbial mass-specific respiration, which increased 2.1-fold under manure exposure. These findings demonstrate that the maintenance of antibiotic resistance associated with manure inputs alters soil microbial communities and ecosystem function.

opencc-by-4.0Oct 2023View details →

Assemblies for 'Mixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients'

Antibiotic resistance poses a global health threat, but the within-host drivers of resistance remain poorly understood. Pathogen populations are often assumed to be clonal within hosts, and resistance is thought to emerge due to selection for de novo variants. Here we show that mixed strain populations are common in the opportunistic pathogen P. aeruginosa. Crucially, resistance evolves rapidly in patients colonized by multiple strains through selection for pre-existing resistant strains. In contrast, resistance evolves sporadically in patients colonized by single strains due to selection for novel resistance mutations. However, strong trade-offs between resistance and growth rate occur in mixed strain populations, suggesting that within-host diversity can also drive the loss of resistance in the absence of antibiotic treatment. In summary, we show that the within-host diversity of pathogen populations plays a key role in shaping the emergence of resistance in response to treatment.

opencc-zeroOct 2022View details →

Characterization of virulence factors and antibiotic resistance pattern of uropathogenic Escherichia coli strains in a tertiary care center

Background: Urinary tract infections (UTIs) are the most prevalent bacterial infection in humans. The uropathogenic E. coli (UPEC) express a wide range of virulence factors that contribute to their pathogenicity. The emergence of Multidrug resistance(MDR)-associated UTI is increasing off late. Hence this study was undertaken to monitor the distribution of virulence factors among UPEC strains and to note the antibiogram, outcome and type of associated UTI. Methods: A prospective cross-sectional time-bound study of 6 months was done on clinically significant urinary isolates of Escherichia coli. Detection of haemolysin production and serum resistance was done by phenotypic methods. Genotypic characterization of the virulence genes (papC, iutA, hlyA, cnf1) was done by multiplex PCR. Demographic data, clinical history, antibiogram and type of UTI were collected from clinical case records. Results: 75 E. coli isolates from patients with suspected urinary tract infections were included. Females had a higher preponderance of UTI (66.7%).93% of the patients were adults and the remaining 7% were from the paediatric population. 24 (32%) isolates showed haemolysis by plate haemolysis method, and all 75 (100%) isolates were serum resistant. Out of 75 isolates, 65 were positive for at least one of the four targeted genes, while the remaining 10 isolates were negative for all 4 genes. Multidrug resistance was found in 40 (53.3%) isolates. 97.4% of the UTI cases had a favourable clinical outcome at discharge. Mortality due to urosepsis was 2.6%. Conclusion: The association of hemolysin production with resistance to imipenem and norfloxacin in UPEC strains was significant. The presence of the hlyA gene is positively associated with ceftazidime resistance. Nitrofurantoin, piperacillin tazobactam and cefaperazone sulbactam maybe suitable candidates for empirical therapy of UTIs. Drugs like aminoglycosides, carbapenems and fosfomycin may be used as reserve drugs in the treatment of MDR-UTI. However, inappropriate usage can gradually increase antibiotic resistance. Hence, proper selection of antibiotics in hospitals taking into account the local antibiogram is needed to reduce the emergence of antibiotic resistance.

opencc-by-4.0Dec 2021View details →

Supplementary data for "The fitness of beta-lactamase mutants depends nonlinearly on resistance level at sublethal antibiotic concentrations."

Supplementary data files and scripts, notes and figures accompanying the manuscript with working title "The fitness of beta-lactamase mutants depends nonlinearly on resistance level at sublethal antibiotic concentrations". The figures and tables this dataset underpins is indicated in the name of each file of the dataset, or in the section "Code and data accessibility" of the manuscript.

opencc-zeroMar 2023View details →

Data for: Host-specific plasmid evolution explains the variable spread of clinical antibiotic-resistance plasmids

Antibiotic resistance encoded on plasmids is a pressing global health problem. Predicting which plasmids spread in the long term remains very challenging, even though some key parameters influencing plasmid stability have been identified, such as plasmid growth costs and horizontal transfer rates. Here, we show these parameters evolve in a strain-specific way among clinical plasmids and bacteria, and this occurs rapidly enough to alter the relative likelihoods of different bacterium-plasmid combinations spreading. We used experiments with Escherichia coli and antibiotic-resistance plasmids isolated from patients, paired with a mathematical model, to track long-term plasmid stability (beyond antibiotic exposure). Explaining variable stability across six bacterium-plasmid combinations required accounting for evolutionary changes in plasmid-stability traits, whereas initial variation of these parameters was a relatively poor predictor of long-term outcomes. Evolutionary trajectories were specific to particular bacterium-plasmid combinations, as evidenced by genome sequencing and genetic manipulation. This revealed epistatic (here, strain-dependent) effects of key genetic changes affecting horizontal plasmid transfer. Several genetic changes involved mobile elements and pathogenicity islands. Rapid strain-specific evolution can thus outweigh ancestral phenotypes as a predictor of plasmid stability. Accounting for strain-specific plasmid evolution in natural populations could improve our ability to anticipate and manage successful bacterium-plasmid combinations.

opencc-zeroMar 2023View details →

Escaping ESKAPE resistance: In vitro and in silico studies of multifunctional carbamimidoyl-tethered indoles against antibiotic-resistant bacteria

Combining the hybridization and repurposing strategies, six compounds from our in-house library with a designed hybrid structure of MBX-1162, pentamidine and MMV688271 were repurposed as potential antibacterial agents. Amongst them, compounds 1a and 1d elicited potential sub-µg/mL activity against the high-priority antibiotic-resistant Gram-positive members of ESKAPE bacteria as well as antibiotic-susceptible Gram-positive bacteria. Furthermore, they showed potential low µg/mL activity against the explored critical priority antibiotic-resistant Gram-negative members of ESKAPE bacteria. In time-kill assay, compound 1a has effective 0.5 and 0.25 µg/mL antibacterial lethal concentrations against MRSA in the exponential growth phase. In silico investigations predicted compounds 1a and 1d as inhibitors of the open conformation of undecaprenyl diphosphate synthase involved in bacterial isoprenoid synthesis. In addition, compounds 1a and 1d were predicted as inhibitors of the NADPH-free but not the NADPH-bound form of ketol-acid reductoisomerase and may also serve as potential B-DNA minor groove binders with possible differences in the molecular sequence recognition. Overall, compounds 1a and 1d are presented as multifunctional potential antibacterial agents for further development against high and critical-priority Gram-positive and Gram-negative antibiotic-resistant ESKAPE bacterial pathogens as well as antibiotic-susceptible Gram-positive bacterial pathogens.

Figure 4: Antibiotic sensitivity and resistance pattern of Enterococcus faecium

Figure 4: Antibiotic sensitivity and resistance pattern of Enterococcus faecium

Figure 19: Antibiotic sensitivity and resistance pattern of Enterobacter spp

Figure 19: Antibiotic sensitivity and resistance pattern of  Enterobacter spp

Figure 16: Antibiotic sensitivity and resistance pattern of Pseudomonas aeruginosa

Figure 16: Antibiotic sensitivity and resistance pattern of  Pseudomonas aeruginosa

Fig13: Antibiotic sensitivity and resistance pattern of Acinetobacter Baumannii

Fig13: Antibiotic sensitivity and resistance pattern of Acinetobacter Baumannii

Figure 10: Antibiotic sensitivity and resistance pattern of Klebsiella pneumoniae

Figure 10: Antibiotic sensitivity and resistance pattern of Klebsiella pneumoniae

Figure 7: Antibiotic sensitivity and resistance pattern of Staphylococcus Aureus

Figure 7: Antibiotic sensitivity and resistance pattern of Staphylococcus Aureus