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Training and Research AImed at Novel Antibacterial Solutions in Animals and People

Final Report Summary - TRAIN-ASAP (Training and Research AImed at Novel Antibacterial Solutions in Animals and People)

TRAIN-ASAP addressed a very urgent public health issue deriving from the rise of antimicrobial resistance, the lack of effective antibacterial drugs to cure infections caused by multidrug-resistant (MDR) bacteria, and the animal welfare and zoonotic consequences associated with the emergence of some of these MDR bacteria in animals, including livestock and companion animals. The growing evidence that antimicrobial resistance may be transmitted from animals and humans, by either consumption of contaminated food or direct exposure to living animals, has enforced the traditional debate on the appropriateness of using antimicrobials in livestock production and veterinary medicine. Among the possible measures to limit the risk of zoonotic transmission of antimicrobial resistance, it is important to optimize antimicrobial use in animals as well as to develop alternative veterinary-specific drugs and strategies to manage bacterial infections.

The objective of TRAIN-ASAP was to fill the gap between the burden of infections due to multidrug-resistant bacteria and the strong need for innovative solutions to combat antimicrobial resistance in both humans and animals. The objective was pursued using a typical One Health approach recognizing that the health of people is connected to the health of animals. Twelve Early Stage Researchers (ESRs) were trained in the scientific and complementary skills needed to implement a broad range of antibacterial strategies including discovery of new antibiotics, synthesis of antimicrobial peptides with improved pharmacological properties, improvement of the efficacy of currently known drugs, and alternative strategies based on phages, bacteriocin-producing organisms, and antibiotic-neutralizing products aimed at reducing selection of antimicrobial resistance in the intestinal microbiota.
Work performed and main results

Twelve ESRs from 9 countries were employed in the fall of 2012. Each ESR, including the 3 ESRs employed by the private partners, was enrolled in a PhD program. Three additional ESRs funded by the University of Copenhagen joined the network and actively participated in the training activities of TRAIN-ASAP, contributing to increase the critical mass of the project. The goal of TRAIN-ASAP was to meet the demand for a new generation of antibacterial drug experts through a unique training program combining academic and industrial work experience. Postgraduate training of young researchers in using the high-throughput technology, chemical libraries and screening funnels available within the partner industries was combined with direct industrial experience on the discovery, development, and regulatory requirements necessary for the delivery of new antibacterial products to the market.

The training objectives of TRAIN-ASAP program were i) to establish a comprehensive multidisciplinary and intersectorial One Health training programme focusing on novel and sustainable solutions to address the growing problem of antimicrobial resistance in human and veterinary medicine; and ii) to provide the ESRs with a wide range of technological and professional skills required to work in academia, the pharmaceutical industry as well as other governmental and international regulatory agencies involved in the area of public or animal health. Appropriate tutorial training was provided to the ESRs depending on their individual backgrounds and training needs. A personalized ESR training program comprising a research project, course work, development of teaching, communication and writing skills, participation in a research school, secondment, and public defense of a PhD thesis, was integrated with a series of network-wide training events specifically designed to achieve the training objectives of the ITN. The ITN network-wide program culminated with the organization of the 1st International Conference on One Health Antimicrobial Resistance (ICOHAR, which hosted over 120 registered attendees from 61 institutions and 15 countries. This conference provided the ESRs with the opportunity to present the final results of their research projects in front of a qualified audience composed by scientists and stakeholders. All ESRs had one or multiple secondments at prestigious academic institutions or world-leading enterprises, facilitating multidisciplinary training of the ESRs and knowledge sharing between academic and industrial partners. Among the 12 ESRs, 7 defended their PhD thesis in due time, 3 are likely to graduate after the end of the ITN, and 2 failed to complete their PhD programs.

The TRAIN-ASAP research program was structured into three scientific work packages aimed at the discovery and development of new antibacterial drugs (WP1), improvement of the clinical efficacy of existing antibacterial drugs (WP2) and development of alternative non-antibiotic antibacterial strategies for specific veterinary applications (WP3). Each WP included diverse research projects (RPs) targeting the same objective using complementary approaches. In WP1, several cyclic antimicrobial peptides and peptide-peptoid hybrids were synthesized and characterized for their activity against key human (RP1) and veterinary pathogens (RP2), respectively. The metabolic potential of the recently described genus Actinoallomurus was explored, leading to the identification of specific strains producing a new active compounds (RP3). A culture-independent approach was developed to detect secondary metabolite gene clusters in the non-culturable fraction of the soil microbiota (RP4). Actinomycete secondary metabolites were characterized for their ability to interfere with virulence gene expression (RP5).
WP2 was designed to improve the efficacy of three distinct classes of existing antimicrobial classes: macrolides, sulphonamides and aminoglycosides. An in vitro model was developed to study the pharmacodynamics of veterinary macrolides in Actinobacillus pleuropneumoniae with the ultimate goal to optimize therapy of this important pathogen in pig production (RP6). The ratio for combinations of sulfonamides and trimethoprim was optimized for equine treatment and antimicrobial susceptibility testing of streptococcal infections in horses, and novel targets inhibiting the folate pathway were studied for veterinary applications (RP7). A new strategy to improve the efficacy of aminoglycoside antibiotics by inhibiting a mechanism of aminoglycoside resistance was explored at the genetic level (RP8). Finally, WP3 focused on alternative non-antibiotic strategies in veterinary medicine. Several strains with an inhibitory effect on the pig pathogen Streptococcus suis have be isolated and are currently characterized at the molecular level (RP9). Phages that are able to kill avian pathogenic Escherichia coli (RP10) and the canine pathogen Staphylococcus pseudintermedius (RP11) were isolated and characterized to assess specific veterinary applications. Finally, various formulations were tested and two pharmacokinetic studies, one in dogs and one in veal calves, were performed to develop veterinary products able to prevent selection of antimicrobial resistance in the intestinal tract of animals treated with marbofloxacin (RP12).

Considering the urgent need for new drugs to combat antimicrobial resistance and the growing demand for skilled scientists specialized in antibacterial drug discovery, the ESRs are expected to have excellent job opportunities. Indeed, some of them found a job in the academia or in the pharmaceutical industry immediately after their PhD graduation and prior to the end of the ITN. The One Health nature of TRAIN-ASAP has contributed to reduce sectorial and disciplinary boundaries in this area, notably through the promotion of multidisciplinary research, international collaboration, knowledge transfer between human and veterinary sectors, and industry-academia cooperation. The newly discovered antibacterial molecules generated spin-offs of great benefit to the two SMEs participating in the ITN. Some of the findings generated by the ITN have been patented or are presently investigated for possible clinical applications in human or veterinary medicine. Academic and industry partners are still collaborating on some of the research projects initiated by the ESRs, resulting in a durable European training programme that transcended the duration of the ITN.