EAR - Effects of antibiotic resistance on bacterial fitness, virulence and transmission

EC contribution: : € 2.755.000
Duration: : 36 months
Starting date: : 01/12/2005
Funding scheme: : Specific Targeted Research Project
Keywords: : antibiotic resistance, fitness, genetic compensation, transmission, virulence
Contract/Grant agreement number: : LSHM-CT-2005-518152
Project web-site: : -

Background:

A major factor that affects the emergence and survival of resistant strains is the biological cost of resistance. Thus, to reduce the rate of spread of resistant bacteria we need to identify antibiotic targets and antibiotics for which the resistance mechanisms have the most negative effects on bacterial fitness. Thus, the overall aims of this proposal are to experimentally examine and define in several medically important species how fitness, virulence and transmission are affected by different types of antibiotic resistance. Such knowledge is a prerequisite for: (i) predicting the rate and stability of resistance development, (ii) developing novel diagnostic test systems for resistant bacterial clones with a high risk of resistance development, (iii) forecasting the value of intervention strategies and (iv) rational design of antibiotics and choice of antibiotic targets where the potential for resistance development is minimized.

Problem:

Ever since antibiotics were first introduced 60 years ago they have been a remarkable success story giving us the opportunity to treat and cure most infectious diseases. However, the intensive use and inappropriate use of antibiotics has also resulted in the many important human pathogens developing resistance. There is a concern that in time that the loss of therapeutic options will present us with a post-antibiotic era where present and future medical advances are threatened. The combination of a worldwide rapid increase in resistant bacteria and the downward trend in the development of new antibiotics has serious implications. Resistant bacteria dramatically reduce the possibilities of treating infections effectively and increase the risk of complications and fatal outcome for patients with severe infections. Those most vulnerable patients are children, the elderly and the economically disadvantaged. Individuals with compromised immune defences, such as cancer patients and those living with HIV require antibiotic therapy to prevent and treat severe infections and these drugs are necessary for their survival. In addition, antibiotic resistance jeopardises advanced medical procedures such as organ transplantation and implants of prostheses, where infective complications are common and antibiotic therapy is necessary to prevent or treat complications. Thus, antibiotic resistance represents a major public health concern and economic problem.

Aim:

1) The first objective is to experimentally determine how different types of antibiotic resistances affect fitness (growth and survival within and outside hosts) of several pathogenic bacterial species. In particular, we will determine if antibiotic resistance can truly be cost free for a bacterium. Putative cost-free mutations are expected to be especially problematic and stable in the population.

2) The second objective is to determine the physiological reasons for why fitness is reduced in antibiotic resistant mutant bacteria. Using global approaches (microarrays and proteomics) we intend to determine how gene expression and metabolism is changed as a result of the acquisition of a resistance determinant. In particular, we will examine why the same resistance mechanism/mutation might have very different physiological effects in different species. An understanding of the specific nature of the fitness defects could reveal weaknesses in the resistant bacteria exploitable either by alternative or supplementary therapies or by novel antibiotics.

3) The third objective is to determine if the fitness costs of resistance can be reduced by mutation and/or environmental conditions. Thus, we will examine the rate at which compensatory mutations ameliorate fitness deficit both in vitro and in vivo. Thus, the objective will be to understand the link between the fitness cost of resistance and cost compensation making use of appropriate animal model systems.

4) The fourth objective is to develop animal experimental models to study the impact of resistance on transmission rates.

5) The fifth objective is to use volunteer studies to examine the impact of antibiotic resistance on transmission rates.

6) The sixth objective is to use epidemiological data to examine in a real clinical situation if and how the basic reproductive number (the number of secondary infections generated from an infected individual) is altered due to the acquisition of antibiotic resistance.

7) The seventh objective is to perform a unique clinical intervention study where the use of an antibiotic will be significantly curtailed in a community in an attempt to reduce the frequency of resistant bacteria.

8) Finally, in the eighth objective we want to investigate two new concepts experimentally in the development and selection of drugs and drug targets where the likelihood of resistance development is reduced. First, the "multiple targets concept" where the drugs have multiple targets in the bacterial cell, making the development of resistance due to target alterations very difficult. Second, the "high pleiotropic biological cost" concept. That is, novel drugs and drug targets are designed and chosen such that the resistance mechanisms severely reduce pathogen fitness by interfering with bacterial physiology at many different levels. We will explore as a model system how resistance to different variants of fusidic acid affects fitness.

Expected and obtained results:

The results obtained from this network of researchers will (1) provide the experimental knowledge required to model and perform risk assessment for the development, and spread of resistance to any given antibiotic. The achievements made here will also form the (2) knowledge base required to formulate and to interpret intervention strategies which attempt to reduce the rate of resistance development and achieve a reversal of the rising tide of resistance in the society. The approaches suggested in this proposal will be useful for pharmaceutical companies and drug-licensing agencies when they assess the potential risk for resistance development towards both new and established antibiotics. Finally, the methodology and approaches proposed in this application will make it possible to (3) identify particular attributes in high-risk resistant bacteria (e.g. clones that have no fitness cost for being resistant) allowing for their rapid dissemination in the community, and hence provide the basis for early warning diagnostic systems forecasting rapidly spreading resistant clones. By identifying attributes in susceptible bacteria predisposing for rapid and stable resistance development this proposal promises to provide the knowledge base on which to develop diagnostic systems forecasting resistance development within susceptible bacterial communities.

Potential applications:

Antibiotic resistance is a serious problem that creates a substantial mortality, morbidity and health care cost. In intensive care units recent studies have shown that inadequate antibiotic therapy related to antibiotic resistance causes up to four times higher mortality as well as considerable added costs. From this perspective, the completion of the objectives of this project should certainly influence several social objectives of the Community. Antibiotic resistant organisms should thus be considered as dangerous spreading organisms that may affect the health of the community. In particular, an important part of the currently available medical technology, including advanced surgery, transplantation, therapies for cancer and immuno-deficiencies, and intensive care units, depends on the successful control of microorganisms by antimicrobial agents, and the safety of all these procedures depends on the maintenance of effective antibiotic treatments. The deliverables of this proposal will aid in the development of guidelines for the clinical use and regulation of antibiotics which may help free resources for other important health issues of EU citizens.

During the antibiotic era the molecular mechanisms for resistance to a large variety of antibacterial agents have been elucidated. However, it is only recently that population dynamics and evolutionary engineering approaches have been taken to describe the development and reversibility of bacterial resistance. Recent advances from the HIV field have taught us that population sizes, rates of growth, and rates of genetic variation, within different cellular compartments in a host, determines the likelihood of resistance development and hence the prognosis of the patient. By adopting population dynamic and evolutionary approaches also towards bacterial antibiotic resistance we have the possibility to develop tools as a base for any future predictions of the spread of antibiotic resistance. For that a purpose we need to consider the size of any given bacterial population, mutation rates, rate of genetic lateral flow between bacteria, biological costs of resistance, transmission rates and virulence in order to formulate mathematical models describing resistance development under various assumptions. Without an understanding of the above parameters it will not be possible to properly develop local, national or European strategies to counteract the rapidly increasing problem of antibiotic resistance.

Coordinator:

Prof. Dan I. Andersson
Uppsala University
Department of Medical Biochemistry and Microbiology
Box 582, BMC
751 23 Uppsala, Sweden
Tel. +46 18 471 4175
Fax +46 18 509 876
Dan.Andersson@imbim.uu.se

European Commission