Zusammenfassung
Antimikrobielle Resistenzen (AMR) entwickeln sich weltweit zum ernsten Problem für das Gesundheitswesen. Über Jahrzehnte hinweg wurde nur unzureichend an der Erforschung grundlegend neuer Antibiotika gearbeitet, folglich erreichten nur wenige Präparate den Markt. Der Druck ist seither enorm gewachsen, neue wirksame Konzepte zur Reduktion von Infektionen durch Problemerreger zu implementieren. Von politischer Seite wurde diese Dringlichkeit erkannt und umfangreiche Förderprogramme wurden sowohl national als auch international ins Leben gerufen. Eine tragende Säule vieler öffentlich finanzierter Maßnahmen ist die Erforschung und Entwicklung von Therapeutika, deren Wirkungen auf neuen Mechanismen beruhen und/oder die Bildung von Resistenzen minimieren. Neben der aktuellen klinischen Entwicklungspipeline werden in diesem Artikel ausgewählte Beispiele aus der Forschung und frühen Entwicklung aufgeführt. Der Fokus liegt hierbei auf Antibiotika, aber auch Alternativen wie Antivirulenz- und Phagentherapie sowie Immunmodulatoren werden in Ansätzen diskutiert. AMR ist längst kein rein gesundheitspolitisches Problem mehr, sondern von gesamtgesellschaftlicher Bedeutung. Es ist daher dringend geboten, Forschungsinfrastrukturen und öffentlich-private Partnerschaften zu stärken, regulatorische Hürden abzubauen und Innovationen für die antimikrobielle Therapie mit Hochdruck voranzutreiben.
Abstract
Antimicrobial resistance (AMR) has developed into a serious problem for the healthcare sector worldwide. Research on fundamentally novel antibiotics has been insufficient for decades and only a few new compounds have reached the market. Thus, the pressure to implement novel and effective concepts for the reduction of infections through problematic pathogens has dramatically increased. This demand has been recognized by politicians and comprehensive national and international funding programs have been launched. A major role of many funding lines is the investigation and development of therapeutics exerting a novel mechanism of action and/or minimizing the frequency of resistance. In addition to the actual clinical pipeline, this article lists selected examples from research and early development with a special focus on antibiotics. Moreover, alternative approaches like antivirulence and phage therapy as well as immunomodulation are summarized. AMR is no longer solely a healthcare policy, but is of societal significance as a whole. A consolidation of infrastructures and public-private partnerships, a reduction of regulatory obstacles and a continuous pursuit of innovations for antimicrobial therapy are urgently needed.
Literatur
Kupferschmidt K (2017) Resistance figthers. Science 352:758–761
World Bank (2016) Drug-Resistant Infections: A Threat to Our Economic Future (Discussion Draft). Washington, DC
WHO (2015) Global action plan on antimicrobial resistance. WHO, Geneva
CARA (2016) An Alliance to Support the U.N. resolution on antimicrobial resistance: CARA: the conscience of antimicrobial resistance accountability
The Federal Government (2015) DART 2020 Fighting antibiotic resistance for the good of both humans and animals. The Federal Government, Berlin
Bundesministerium für Gesundheit (2017) DART 2020, 2. Zwischenbericht. Bundesministerium für Gesundheit, Berlin
WHO (2017) Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis. WHO, Geneva
Cooper MA, Shlaes D (2011) Fix the antibiotics pipeline. Nature 472:32–32
O’shea R, Moser HE (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51:2871–2878
Tommasi R, Brown DG, Walkup GK, Manchester JI, Miller AA (2015) ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov 14:529–542
Fernandes P, Martens E (2017) Antibiotics in late clinical development. Biochem Pharmacol 133:152–163
Global Union for Antibiotics Research and Development (GUARD) Initiative Commissioned by the German Federal Ministry of Health (2015) Breaking through the wall. German Federal Ministry of Health, Berlin
Boston Consulting Group, Federal Ministry of Health (2017) Follow-up report for the German GUARD initiative: “Breaking through the wall”. Federal Ministry of Health, Berlin
Rex JH, Outterson K (2016) Antibiotic reimbursement in a model delinked from sales: a benchmark-based worldwide approach. Lancet Infect Dis 16:500–505
https://clinicaltrials.gov. Zugegriffen: 01.01.2018
https://www.nabriva.com/pipeline-research. Zugegriffen: 21.03.2018
http://www.entasistx.com/pipeline. Zugegriffen: 21.03.2018
https://www.summitplc.com/programmes/c-difficile-infections. Zugegriffen: 21.03.2018
http://www.sequella.com/pipeline. Zugegriffen: 21.03.2018
https://www.polyphor.com/pol7080. Zugegriffen: 21.03.2018
https://www.gsk-clinicalstudyregister.com/compounds/gepotidacin/all/1. Zugegriffen: 21.03.2018
https://www.debiopharm.com/our-business/pipeline/item/3392. Zugegriffen: 21.03.2018
http://www.crystalgenomics.com/en/clinical/antibiotic.html. Zugegriffen: 21.03.2018
http://www.ipharminc.com/brilacidin-1. Zugegriffen: 21.03.2018
https://www.destinypharma.com/platform/xf-73-exeporfinium-chloride. Zugegriffen: 21.03.2018
http://www.mgb-biopharma.com/programs-overview-2. Zugegriffen: 21.03.2018
https://sperotherapeutics.com/pipeline. Zugegriffen: 21.03.2018
https://www.gsk-clinicalstudyregister.com/compounds/gsk3036656/all. Zugegriffen: 21.03.2018
http://www.qurient.com/?page_id=36238&lang=en. Zugegriffen: 21.03.2018
http://www.newtbdrugs.org/pipeline/compound/macozinonone-mcz-pbtz-169. Zugegriffen: 21.03.2018
http://www.cptrinitiative.org/wp-content/uploads/2017/05/Jeffrey_Hafkin_CPTR2017_JH.pdf. Zugegriffen: 21.03.2018
https://www.tballiance.org/portfolio/compound/tba-7371-dpre1-inhibitor. Zugegriffen: 21.03.2018
http://www.crestonepharma.com/index.php/cdi. Zugegriffen: 21.03.2018
https://www.venatorx.com. Zugegriffen: 21.03.2018
The PEW Charitable Trusts (2017) Antibiotics currently in clinical development
European Observatory on Health Systems and Policies (2016) Targeting innovation in antibiotic drug discovery and development. European Observatory on Health Systems and Policies, London
Cahill ST, Cain R, Wang DY et al (2017) Cyclic boronates inhibit all classes of beta-lactamases. Antimicrob Agents Chemother 61:e2260–e2216
Blaskovich MA, Butler MS, Cooper MA (2017) Polishing the tarnished silver bullet: the quest for new antibiotics. Essays Biochem 61:103–114
Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661
Tang X, Li J, Millan-Aguinaga N et al (2015) Identification of thiotetronic acid antibiotic biosynthetic pathways by target-directed genome mining. Acs Chem Biol 10:2841–2849
Wohlleben W, Mast Y, Stegmann E, Ziemert N (2016) Antibiotic drug discovery. Microb Biotechnol 9:541–548
Scherlach K, Hertweck C (2009) Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem 7:1753–1760
Ling LL, Schneider T, Peoples AJ et al (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517:455–459
Guo CJ, Chang FY, Wyche TP et al (2017) Discovery of reactive microbiota-derived metabolites that inhibit host proteases. Cell 168:517–526
Pidot SJ, Coyne S, Kloss F, Hertweck C (2014) Antibiotics from neglected bacterial sources. Int J Med Microbiol 304:14–22
Cooper MA (2015) A community-based approach to new antibiotic discovery. Nat Rev Drug Discov 14:587–588
Seiple IB, Zhang Z, Jakubec P et al (2016) A platform for the discovery of new macrolide antibiotics. Nature 533:338–345
Wright PM, Seiple IB, Myers AG (2014) The evolving role of chemical synthesis in antibacterial drug discovery. Angew Chem Int Ed Engl 53:8840–8869
Kling A, Lukat P, Almeida DV et al (2015) Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348:1106–1112
Rajamuthiah R, Fuchs BB, Conery AL et al (2015) Repurposing salicylanilide anthelmintic drugs to combat drug resistant staphylococcus aureus. PLoS ONE 10:e124595
Richter MF, Drown BS, Riley AP et al (2017) Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545:299–304
Wagner S, Sommer R, Hinsberger S et al (2016) Novel strategies for the treatment of pseudomonas aeruginosa infections. J Med Chem 59:5929–5969
Sass P, Josten M, Famulla K et al (2011) Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc Natl Acad Sci Usa 108:17474–17479
Gersch M, Famulla K, Dahmen M et al (2015) AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control. Nat Commun 6:6320–6331
Lehar SM, Pillow T, Xu M et al (2015) Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. Nature 527:323–328
Klahn P, Bronstrup M (2017) Bifunctional antimicrobial conjugates and hybrid antimicrobials. Nat Prod Rep 34:832–885
Czaplewski L, Bax R, Clokie M et al (2016) Alternatives to antibiotics – a pipeline portfolio review. Lancet Infect Dis 16:239–251
Drew L (2016) Microbiota: reseeding the gut. Nature 540:S109–S112
Reardon S (2014) Phage therapy gets revitalized. Nature 510:15–16
Pirisi A (2000) Phage therapy – advantages over antibiotics? Lancet 356:1418
Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28:591–595
Fox JL (2013) Antimicrobial peptides stage a comeback. Nat Biotechnol 5:379–382
Fjell CD, Hiss JA, Hancock RE, Schneider G (2011) Designing antimicrobial peptides: form follows function. Nat Rev Drug Discov 11:37–51
Hancock RE, Haney EF, Gill EE (2016) The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol 16:321–334
Dickey SW, Cheung GYC, Otto M (2017) Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov 16:457–471
De La Fuente-Nunez C, Reffuveille F, Mansour SC et al (2015) D‑enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal pseudomonas aeruginosa infections. Chem Biol 22:196–205
EDCTP (2017) Annual report 2016. EDCTP, The Hague
Global Antibiotic Research & Development Partnership (2016) Business plan 2017–2023. GARDP, Geneva
Mullard A (2017) Preclinical antibiotic pipeline gets a pick-me-up. Nat Rev Drug Discov 16:741–742
Bundesministerium für Gesundheit (2016) Bericht zu den Ergebnissen des Pharmadialogs. Bundesministerium für Gesundheit, Berlin
Danksagung
Wir danken dem Bundesministerium für Bildung und Forschung (BMBF) im Rahmen der Konsortien InfectControl 2020 und dem Leibniz Research Cluster Bio/synthetische multifunktionale Mikroproduktionseinheiten – Neue Wege der Wirkstoff-Entwicklung sowie dem Freistaat Thüringen für finanzielle Unterstützung.
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F. Kloß und S. Gerbach geben an, dass kein Interessenkonflikt besteht.
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Kloß, F., Gerbach, S. Hürden und Aussichten neuer antimikrobieller Konzepte in Forschung und Entwicklung. Bundesgesundheitsbl 61, 595–605 (2018). https://doi.org/10.1007/s00103-018-2725-z
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DOI: https://doi.org/10.1007/s00103-018-2725-z