A ‘time bomb’ in the human intestine—the multiple emergence and spread of antibiotic-resistant bacteria

Antibiotics have a strong killing effect on bacteria and are the first choice for the prevention and treatment of bacterial infectious diseases. Therefore, they have been widely used in the medical field, animal husbandry and planting industry. However, with the massive use of antibiotics, more and more antibiotic-resistant bacteria (ARB) have emerged. Because human intestines are rich in nutrients, have suitable temperature, and are high in bacterial abundance, they can easily become a hotbed for the spread of ARB and antibiotic-resistant genes (ARGs). When opportunistic pathogenic bacteria in the intestine acquire ARGs, the infectious diseases caused by such opportunistic pathogens will become more difficult to treat, or even impossible to cure. Therefore, ARB in the human intestine are like a ‘time bomb’. In this review, we discuss the sources of intestinal ARB and the transmission routes of ARGs in the human intestine from the perspective of One Health. Further, we describe various methods to prevent the emergence of ARB and inhibit the spread of ARGs in the human intestine. Finally, we may be able to overcome ARB in the human intestine using an interdisciplinary ‘One Health’ approach.     

The role of non-biting flies in the epidemiology of human infectious diseases

The feeding and reproductive habits of non-biting synanthropic flies make them important mechanical vectors of human pathogens. Synanthropic flies are major epidemiologic factors responsible for the spread of acute gastroenteritis and trachoma among infants and young children in (predominantly) developing countries. House flies are involved in mechanical transmission of nosocomial infections with multiple antibiotic-resistant bacteria in hospital environments.     

New sequence types and multidrug resistance among pathogenic Escherichia coli isolates from coastal marine sediments

The spread of antibiotic-resistant microorganisms is widely recognized, but data about their sources, presence, and significance in marine environments are still limited. We examined 109 Escherichia coli strains from coastal marine sediments carrying virulence genes for antibiotic susceptibility, specific resistance genes, prevalence of class 1 and 2 integrons, and sequence type. Antibiotic resistance was found in 35% of strains, and multiple resistances were found in 14%; the resistances detected most frequently were against tetracycline (28%), ampicillin (16.5%), trimethoprim-sulfamethoxazole (13%), and streptomycin (7%). The highest prevalence of resistant strains was in phylogenetic group A, whereas phylogroup B2 exhibited a significantly lower frequency than all the other groups. Sixty percent of multiresistant strains harbored class 1 or 2 integrase genes, and about 50% carried resistance genes (particularly dfrA and aadA) linked to a class 1 integron. Multilocus sequence typing of 14 selected strains identified eight different types characteristic of extraintestinal pathogens and three new allelic combinations. Our data suggest that coastal marine sediment may be a suitable environment for the survival of pathogenic and antimicrobial-resistant E. coli strains capable of contributing to resistance spread via integrons among benthic bacteria, and they highlight a role for these strains in the emergence of new virulent genotypes.     

Enhancing the antibiotic antibacterial effect by sub lethal tellurite concentrations: tellurite and cefotaxime act synergistically in Escherichia coli

The emergence of antibiotic-resistant pathogenic bacteria during the last decades has become a public health concern worldwide. Aiming to explore new alternatives to treat antibiotic-resistant bacteria and given that the tellurium oxyanion tellurite is highly toxic for most microorganisms, we evaluated the ability of sub lethal tellurite concentrations to strengthen the effect of several antibiotics. Tellurite, at nM or μM concentrations, increased importantly the toxicity of defined antibacterials. This was observed with both gram negative and gram positive bacteria, irrespective of the antibiotic or tellurite tolerance of the particular microorganism. The tellurite-mediated antibiotic-potentiating effect occurs in laboratory and clinical, uropathogenic Escherichia coli, especially with antibiotics disturbing the cell wall (ampicillin, cefotaxime) or protein synthesis (tetracycline, chloramphenicol, gentamicin). In particular, the effect of tellurite on the activity of the clinically-relevant, third-generation cephalosporin (cefotaxime), was evaluated. Cell viability assays showed that tellurite and cefotaxime act synergistically against E. coli. In conclusion, using tellurite like an adjuvant could be of great help to cope with several multi-resistant pathogens.     

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

SUMMARY

Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.     

水平基因转移介导抗菌素耐药性传播机制的研究进展

近几十年来,病原菌耐药性的出现和蔓延已上升为严峻的公共卫生问题。越来越多研究表明,抗菌素抗性基因(antibiotic resistance genes,ARGs)不仅仅见于临床所分离的病原体,而是包括所有的致病菌、共生菌以及环境中的细菌,它们都能在可移动遗传元件和噬菌体的作用下,通过水平基因转移(horizontal gene transfer,HGT)途径获得耐药性,进而形成抗菌素耐药基因簇(耐药基因组)。HGT可导致抗菌素的耐药性在环境共生菌和病原菌之间传播扩散,这可通过临床上一些重要的抗菌素耐药基因的传播证实。传统观念认为HGT的三种机制中,接合对ARGs的传播影响最大,最近研究表明转化和转导对ARGs播散起到不可忽视的作用。通过深入了解耐药基因组的传播及其在动员病原菌耐药中发挥的作用,对于控制这些基因的播散是至关重要的。将讨论耐药基因组的概念,提供临床相关的抗菌素抗性基因水平基因转移的例子,对当前已研究的促使抗菌素耐药性传播的各种HGT机制进行回顾。     

细菌自然转化的机制及影响因素

水平基因转移对耐药基因传播、编码毒素基因质粒的扩散和毒力岛的转移等过程具有重要的生物学意义。自然转化是指具有感受态的细菌从外界摄取并整合裸露DNA,是水平基因转移的方式之一。细菌发生自然转化极大地促进了耐药基因在不同细菌间的播散,导致细菌对抗生素耐药,给临床治疗带来极大的困难。许多细菌具备自然转化能力,但不同细菌自然转化过程存在着差异。细菌自然感受及转化的诱发及效率亦受到多种因素的影响。文中着重于阐述不同细菌的自然转化机制及其影响因素。     

Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models.

The emergence of antibiotic resistance in a wide variety of important pathogens of humans presents a worldwide threat to public health. This paper describes recent work on the use of mathematical models of the emergence and spread of resistance bacteria, on scales ranging from within the patient, in hospitals and within communities of people. Model development starts within the treated patient, and pharmacokinetic and pharmacodynamic principles are melded within a framework that mirrors the interaction between bacterial population growth, drug treatment and the immunological responses targeted at the pathogen. The model helps identify areas in which more precise information is needed, particularly in the context of how drugs influence pathogen birth and death rates (pharmacodynamics). The next area addressed is the spread of multiply drug-resistant bacteria in hospital settings. Models of the transmission dynamics of the pathogen provide a framework for assessing the relative merits of different forms of intervention, and provide criteria for control or eradication. The model is applied to the spread of vancomycin-resistant enterococci in an intensive care setting. This model framework is generalized to consider the spread of resistant organisms between hospitals. The model framework allows for heterogeneity in hospital size and highlights the importance of large hospitals in the maintenance of resistant organisms within a defined country. The spread of methicillin resistant Staphylococcus aureus (MRSA) in England and Wales provides a template for model construction and analysis. The final section addresses the emergence and spread of resistant organisms in communities of people and the dependence on the intensity of selection as measured by the volume or rate of drug use. Model output is fitted to data for Finland and Iceland and conclusions drawn concerning the key factors determining the rate of spread and decay once drug pressure is relaxed.     

Food commensal microbes as a potentially important avenue in transmitting antibiotic resistance genes

The rapid emergence of antibiotic-resistant (ART) pathogens is a major threat to public health. While the surfacing of ART food-borne pathogens is alarming, the magnitude of the antibiotic resistance (AR) gene pool in food-borne commensal microbes is yet to be revealed. Incidence of ART commensals in selected retail food products was examined in this study. The presence of 10(2)-10(7) CFU of ART bacteria per gram of foods in many samples, particularly in ready-to-eat, 'healthy' food items, indicates that the ART bacteria are abundant in the food chain. AR-encoding genes were detected in ART isolates, and Streptococcus thermophilus was found to be a major host for AR genes in cheese microbiota. Lactococcus lactis and Leuconostoc sp. isolates were also found carrying AR genes. The data indicate that food could be an important avenue for ART bacterial evolution and dissemination. AR-encoding plasmids from several food-borne commensals were transmitted to Streptococcus mutans via natural gene transformation under laboratory conditions, suggesting the possible transfer of AR genes from food commensals to human residential bacteria via horizontal gene transfer.     

After genomics,what proteomics tools could help us understand the antimicrobial resistance of Escherichia coli?

Proteomic approaches have been considerably improved during the past decade and have been used to investigate the differences in protein expression profiles of cells grown under a broad spectrum of growth conditions and with different stress factors including antibiotics. In Europe, the most significant disease threat remains the presence of microorganisms that have become resistant to antimicrobials and so it is important that different scientific tools are combined to achieve the largest amount of knowledge in this area of expertise. The emergence and spread of the antibiotic-resistant Gram-negative pathogens, such as Escherichia coli, can lead to serious problem public health in humans. E. coli, a very well described prokaryote, has served as a model organism for several biological and biotechnological studies increasingly so since the completion of the E. coli genome-sequencing project. The purpose of this review is to present an overview of the different proteomic approaches to antimicrobial-resistant E. coli that will be helpful to obtain a better knowledge of the antibiotic-resistant mechanism(s). This can also aid to understand the molecular determinants involved with pathogenesis, which is essential for the development of effective strategies to combat infection and to reveal new therapeutic targets. This article is part of a Special Issue entitled: Proteomics: The clinical link.     

The Impact of Different Antibiotic Regimens on the Emergence of Antimicrobial-Resistant Bacteria

Backgroud

The emergence and ongoing spread of antimicrobial-resistant bacteria is a major public health threat. Infections caused by antimicrobial-resistant bacteria are associated with substantially higher rates of morbidity and mortality compared to infections caused by antimicrobial-susceptible bacteria. The emergence and spread of these bacteria is complex and requires incorporating numerous interrelated factors which clinical studies cannot adequately address.

Methods/Principal Findings

A model is created which incorporates several key factors contributing to the emergence and spread of resistant bacteria including the effects of the immune system, acquisition of resistance genes and antimicrobial exposure. The model identifies key strategies which would limit the emergence of antimicrobial-resistant bacterial strains. Specifically, the simulations show that early initiation of antimicrobial therapy and combination therapy with two antibiotics prevents the emergence of resistant bacteria, whereas shorter courses of therapy and sequential administration of antibiotics promote the emergence of resistant strains.

Conclusions/Significance

The principal findings suggest that (i) shorter lengths of antibiotic therapy and early interruption of antibiotic therapy provide an advantage for the resistant strains, (ii) combination therapy with two antibiotics prevents the emergence of resistance strains in contrast to sequential antibiotic therapy, and (iii) early initiation of antibiotics is among the most important factors preventing the emergence of resistant strains. These findings provide new insights into strategies aimed at optimizing the administration of antimicrobials for the treatment of infections and the prevention of the emergence of antimicrobial resistance.     

The digestive tract in immunocompromised patients: importance of maintaining its resistance to colonization,especially in hospital in-patients and those taking antibiotics

The colonization resistance (CR) of the gastrointestinal tract to potential pathogens depends partly on factors within the host but to a greater extent on the normal (anaerobic) gut flora. Its strength varies between individuals. These individual differences in resistance to colonization by pathogenic microorganisms may explain differences in susceptibility to infection. CR is lowered by remission-inducing treatment (radiation and/or chemotherapy) in leukaemia, but more severely by certain antibiotics. Development (by selection or transfer) of resistance to these antibiotics may lead to overgrowth and penetration of the mucosal lining by the overgrowing (potentially) pathogenic bacteria. Other antibiotics however, if sufficiently dosed, have been found to eliminate (potential) pathogens selectively without decreasing CR. This selective decontamination of the gastrointestinal tract has been successfully used prophylactically in neutropenic patients but needs to be monitored bacteriologically. It should perhaps be used more widely in the hospital to control development and spread of antibiotic-resistant strains.     

Seasonal variations in bacterial communities and antibiotic-resistant strains associated with green bottle flies (Diptera: Calliphoridae)

Green bottle flies occur frequently around human environments in Japan. Many species of green bottle flies have been studied with regard to their importance in forensic examinations or clinical therapies, but the bacterial communities associated with this group of flies have not been comprehensively investigated. In this research, 454 pyrosequencing was used to reveal the bacterial communities in green bottle flies collected in different seasons. Meanwhile, the bacteria were screened with selective media and tested for antibiotic susceptibility. Samples collected in three different seasons harbored distinctive bacterial communities. The predominant genera associated with green bottles flies were Staphylococcus in spring, Ignatzschineria in summer, and Vagococcus, Dysgonomonas, and an unclassified Acetobacteraceae in autumn. An upward trend in bacterial community diversity was observed from spring to autumn. Changes in climatic conditions could be the cause of these seasonal variations in fly-associated bacterial communities. The species of isolated antibiotic-resistant bacteria also differed across seasons, but it was difficult to correlate seasonal changes in antibiotic-resistant bacteria with changes in whole communities. A number of multiple-antibiotic-resistant bacteria were isolated, and some of these strains were closely affiliated with pathogens such as Enterococcus faecalis and Enterococcus faecium, which could cause serious threats to public health. Overall, this research provided us with information about the composition and seasonality of bacterial communities in green bottle flies, and highlighted the risks of fly-mediated dissemination of antibiotic-resistant pathogens.     

Enzyme-based formulations for decontamination: current state and perspectives

Development of noncorrosive, cost-effective, environmentally benign, and broad-spectrum antimicrobial formulations is necessary for clinical, industrial, and domestic purposes. Many current decontaminating formulations are effective, but they require the use of strong oxidizing agents or organic solvents that have deleterious effects on human health and the surrounding environment. The emergence of antibiotic-resistant pathogens has motivated researchers to develop enzyme-based self-decontaminating formulations as alternatives to such chemical decontamination approaches. Hydrolytic and oxidative enzymes can be used to deactivate pathogens, including bacteria, spores, viruses, and fungi. Laccases, haloperoxidases, and perhydrolases catalyze the generation of biocidal oxidants, such as iodine, bromine, hypohalous acid (e.g., HOCl or HOBr), and peracetic acid. These oxidants have broad-spectrum antimicrobial activity. Due to the multi-pathway action of these oxidants, it has proven extremely difficult for microbes to gain resistance. Thus far, few examples have been reported on enzyme-based antimicrobial formulations. For these reasons, various enzyme-containing antimicrobial formulations are highlighted in this review.     

噬菌体及其裂解酶在食源性致病菌检测和控制中的应用

微生物致病菌引起的食源性疾病在全世界频频发生,对人类健康造成严重危害,尤其是致病菌耐药性的出现使常规治疗陷入困境。噬菌体及其编码的裂解酶的发现及应用,为食源性致病菌的检测及生物防治开辟了新的途径。综述噬菌体及其裂解酶在构建食源性致病菌的快速检测方法和生物防治方面的应用。     

Enhancement of the efficacy of erythromycin in multiple antibiotic-resistant gram-negative bacterial pathogens

Aims:  To improve the efficacy of erythromycin, a hydrophobic antibiotic, against multiple antibiotic-resistant gram-negative bacterial pathogens by enhancing their outer membrane permeability.
Methods and Results:  Fifty-one nonrepeat gram-negative bacterial pathogens of various genera, resistant to multiple antibiotics, including erythromycin, were selected by disc agar diffusion tests. The amphiphilic cationic steroid antibiotic, Ceragenin CSA-13, a potent permeabilizer of bacterial outer membranes, reduced the minimum inhibitory concentration of erythromycin in 92% of the bacterial pathogens selected for the test, when supplemented with erythromycin. A synergistic effect of Ceragenin CSA-13 and erythromycin in combination was also observed. Spectrofluorimetric study confirmed that Ceragenin CSA-13 acts by depolarizing the bacterial outer membrane. The toxicity of Ceragenin CSA-13 was evaluated to be insignificant by measuring 'median lethal dose' (LD₅₀) on mouse model.
Conclusions:  Ceragenin CSA-13 may be useful as an agent to make erythromycin effective against infections caused by multiple antibiotic resistant gram-negative bacteria.
Significance and Impact of the Study:  The outcome of the study suggests erythromycin–Ceragenin combination as a new approach to overcome the problem associated with the rapid emergence of multi-drug-resistant pathogens. The insignificant toxicity of Ceragenin CSA-13, as found, supports the possibility of the application of this compound for human therapeutics.     

The interaction of bacterial pathogens with platelets

In recent years, the frequency of serious cardiovascular infections such as endocarditis has increased, particularly in association with nosocomially acquired antibiotic-resistant pathogens. Growing evidence suggests a crucial role for the interaction of bacteria with human platelets in the pathogenesis of cardiovascular infections. Here, we review the nature of the interactions between platelets and bacteria, and the role of these interactions in the pathogenesis of endocarditis and other cardiovascular diseases.     

Structure of the Bacterial Deacetylase LpxC Bound to the Nucleotide Reaction Product Reveals Mechanisms of Oxyanion Stabilization and Proton Transfer

The emergence of antibiotic-resistant strains of pathogenic bacteria is an increasing threat to global health that underscores an urgent need for an expanded antibacterial armamentarium. Gram-negative bacteria, such as Escherichia coli, have become increasingly important clinical pathogens with limited treatment options. This is due in part to their lipopolysaccharide (LPS) outer membrane components, which dually serve as endotoxins while also protecting Gram-negative bacteria from antibiotic entry. The LpxC enzyme catalyzes the committed step of LPS biosynthesis, making LpxC a promising target for new antibacterials. Here, we present the first structure of an LpxC enzyme in complex with the deacetylation reaction product, UDP-(3-O-(R-3-hydroxymyristoyl))-glucosamine. These studies provide valuable insight into recognition of substrates and products by LpxC and a platform for structure-guided drug discovery of broad spectrum Gram-negative antibiotics.     

The role of mechanically purified city sewers in the spread of antibiotic-resistant bacteria of the Enterobacteriaceae family

The aim of this study was to evaluate a degree of contribution of mechanically cleansed municipal sewage in a spread in on environment of bacteria of Enterobacteriaceae family with special regard to antibiotic resistant strains. High number of bacteria of Enterobacteriaceae family was found in 1 ml of sewage and the number of antibiotic-resistant bacteria was 0.5-50 X 10(3)/ml. Among the strains tested the resistance to more than one antibiotics was encountered. 78.3% of strains transferred antibiotic resistance to E. coli recipient strain, what indicate a participation of potentially pathogenic bacteria from Enterobacteriaceae family in a spread of antibiotic resistance in a environment.     

Insects Represent a Link between Food Animal Farms and the Urban Environment for Antibiotic Resistance Traits

Antibiotic-resistant bacterial infections result in higher patient mortality rates, prolonged hospitalizations, and increased health care costs. Extensive use of antibiotics as growth promoters in the animal industry represents great pressure for evolution and selection of antibiotic-resistant bacteria on farms. Despite growing evidence showing that antibiotic use and bacterial resistance in food animals correlate with resistance in human pathogens, the proof for direct transmission of antibiotic resistance is difficult to provide. In this review, we make a case that insects commonly associated with food animals likely represent a direct and important link between animal farms and urban communities for antibiotic resistance traits. Houseflies and cockroaches have been shown to carry multidrug-resistant clonal lineages of bacteria identical to those found in animal manure. Furthermore, several studies have demonstrated proliferation of bacteria and horizontal transfer of resistance genes in the insect digestive tract as well as transmission of resistant bacteria by insects to new substrates. We propose that insect management should be an integral part of pre- and postharvest food safety strategies to minimize spread of zoonotic pathogens and antibiotic resistance traits from animal farms. Furthermore, the insect link between the agricultural and urban environment presents an additional argument for adopting prudent use of antibiotics in the food animal industry.