Sumitomo Dainippon Pharma Co., Ltd. Current Situation Regarding External Innovation Infections Caused by Bacteria, Jun HIDAKA with Antimicrobial Resistance Koji TAKEMOTO Isao SHIMIZU (AMR) and KS-Project together with the Kitasato Institute Covered by the Cyclic Innovation for Clinical Empowerment (CiCLE)

The emergence and spread of antimicrobial drug-resistant bacteria has become a global problem. Thus, urgent measures are being called for both at national and international levels. The Kitasato Institute and Sumitomo Dainippon Pharma Co., Ltd. are aiming to provide groundbreaking anti-infective drugs through unprecedented and original approaches, under the KS-Project joint drug discovery research. This paper describes the global problem of antimicrobial drug-resistant bacteria and our antimicrobial drug discovery project covered by the CiCLE.

This paper is translated from R&D Report, “SUMITOMO KAGAKU”, vol. 2019.

Introduction development pipeline for conventional antimicrobial drugs has been quite lacking. The lack of advancement Many antimicrobial drugs that are essential for the in this field is due to the low profitability of antimicro- treatment of bacterial infections were developed in the bial drugs, difficulties in conducting clinical studies of 20th century, and humans appeared to have overcome drugs for the treatment of infections caused by drug- most bacterial infections. However, since the beginning resistant bacteria, and the difficulty of searching for of the 21st century, the emergence and increase of bac- “seeds” of drug discovery. The number of new antimi- teria with antimicrobial resistance (AMR) to many of crobial drugs launched in Japan peaked between 1976 these antimicrobial drugs have become global prob- and 1985 and has since decreased annually2) (Fig. 1). lems. The spread of antimicrobial drug-resistant bacte- ria indicates a return to the days when our lives were Number of drug Antituberculosis at risk because of not only common infections, such as 45 Others Peptide pneumonia, but also infections that occur after simple 40 Macrolide surgery. Furthermore, O’Neill predicted that neglect- 35 Tetracycline ing to take measures for AMR would result in 10 mil- 30 Aminoglycoside Other β-lactam lion annual deaths from infections caused by antimicro- 25 Carbapenem bial drug-resistant bacteria in 2050, which exceed 20 Cephem Penicillins deaths from cancer, and corresponds to an economic 15 loss of 100 trillion US dollars.1) 10 Although the development of antimicrobial drugs 5 that are effective against antimicrobial drug-resistant 0 bacteria has become a globally urgent issue, many 1946-1955 1956-1965 1966-1975 1976-1985 1986-1995 1996-2005 2006-2015 Created using data from cited reference 2). pharmaceutical companies have withdrawn from the field of bacterial infections in recent years, and the Fig. 1 New antibacterial agents launched in Japan

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New β-lactam antimicrobials that are effective against Lumota, launched in West Germany in 1983), cefpi- a wide range of bacterial species have rapidly decreased ramide (brand name Sepatren, launched in 1985), and since 1995, and no new macrolide or cephem antimi- meropenem (brand name Meropen, launched in 1995). crobials were launched between 2006 and 2015. The sit- Furthermore, after the discovery of meropenem, our uation is similar in the United States3); the development company conducted research and development on an of new drugs has stagnated in the field of bacterial anti-MRSA (methicillin-resistant Staphylococcus aureus) infections, and actions against antimicrobial drug-resis- carbapenem (SMP-601) and on oral carbapenem, which tant bacteria are facing a critical situation. has led to joint research with other companies or out- This paper describes the research and development licensing. Although our company temporarily discon- of antimicrobial drugs in our company; provides back- tinued research activities for new drugs after that, the ground information on antimicrobial drug-resistant company has continued the development of in-licensed bacteria and an outline of the mechanism of resistance; products in Japan that had already been approved in discusses global trends, issues, and measures for pro- foreign countries, including liposomal amphotericin B moting the discovery of new antimicrobial drugs; and and ceftaroline, and has conducted supportive research lastly, highlights research on the discovery of drugs for on launched products (Fig. 2). However, because the the treatment of infections caused by antimicrobial global problems of antimicrobial drug-resistant bacte- drug-resistant bacteria that is conducted by the Exter- ria and the need for drugs against these bacteria have nal Innovation of our company, that is, the “KS-Project” been increasing, we believed several years ago that, (Kitasato-Sumitomo Dainippon Antimicrobial Resist- despite significant difficulty, we should restart in-house ance [AMR] Drug Discovery Project), which is a 10- research on drugs with new mechanisms for the treat- year joint research project with the Kitasato Institute ment of infections caused by antimicrobial drug-resis- and covered by the Cyclic Innovation for Clinical tant bacteria and have since been taking action. As Empowerment (CiCLE) of the Japan Agency for Med- mentioned above, we had the proper background for ical Research and Development (AMED). this undertaking: our company had research and devel- opment abilities and know-how that led to the launch Development of Antimicrobial Drugs at of eight antimicrobial drugs including meropenem, Sumitomo Dainippon Pharma Co., Ltd. which can accurately be described as the strongest antimicrobial drug by efficacy and safety and should be Our company has conducted in-house research and considered a human common asset, and we can still uti- development and has launched the following drugs for lize the ability and know-how despite a temporary the treatment of infections: quinolone antimicrobials pending. Furthermore, although the meropenem (oral formulations) including enoxacin (brand name patent has expired and generic versions of this drug Flumark, launched in 1985), sparfloxacin (brand name are selling, the company still sells at least 20 billion yen Spara, launched in 1993), and gatifloxacin (brand name in Japan and China because of its brand power, and new Gatiflo, launched in 2002); and new β-lactam antimicro- drugs in the field can expect to enhance company’s bials (injections) including apalcillin (brand name pipeline. Above all, we thought that our company had

Launched Enoxacin Gatifloxacin

Pipemidic acid Cefpiramide Meropenem Liposomal amphotericin B

Piromidic acid Apalcillin Sparfloxacin

1970 1980 1990 2000 2010

SMP-601 2005 Out-licensed to Oral carbapenem Ceftaroline Licensed/alliance Protez Pharmaceuticals with Fujisawa Pharmaceutical 2011 In-licensed from (Novartis) Takeda Pharmaceutical

Fig. 2 History of antimicrobials developed by Sumitomo Dainippon Pharma Co., Ltd. Blue: β-Lactams, Red: Quinolone, Green: Others

SUMITOMO KAGAKU (English Edition) 2019, Report 5 Copyright © 2019 Sumitomo Chemical Co., Ltd. 2 Current Situation Regarding Infections Caused by Bacteria, with Antimicrobial Resistance (AMR) and KS-Project together with the Kitasato Institute Covered by the Cyclic Innovation for Clinical Empowerment (CiCLE) the social responsibility to develop new drugs for the inhibit the emergence or growth of drug-resistant bac- treatment of infections caused by antimicrobial drug- teria is called the mutant selective window, which the- resistant bacteria. oretically is an environment where drug-resistant bac- teria develop and proliferate most easily. Preventing Antimicrobial Drug-Resistant Bacteria underdosing of antimicrobial drugs is important to avoid exposing pathogenic bacteria to this window for 1. Emergence and Spread of Antimicrobial a long time, and the antimicrobial stewardship is also Drug-Resistant Bacteria important, including treatment with a sufficient dose of Because bacteria rapidly divide, mutations (errors) antimicrobial drugs that are the most suitable to the in genes are more likely to occur in bacterial cells than pathogenic bacteria causing the infection. in animal cells; for example, bacteria obtain resistance by making changes in the target proteins on which 2. Mechanisms of Acquired Antimicrobial antimicrobial drugs act. Moreover, they can transmit Resistance genetic factors between strains using transmissible The major mechanisms of acquired antimicrobial plasmids, transposons, and bacteriophages, and resistance include the following: [1] degrading or mod- obtaining external drug-resistant factors allows the ifying antimicrobial drugs (inactivation), [2] mutations bacteria to obtain a mechanism of resistance that can- in antimicrobial drugs targets (modification), and [3] not be obtained through gene mutations alone. decreasing the concentration of antimicrobial drugs in Although antimicrobial drug-resistant bacteria have the bacteria (pumping out and impermeability) (Fig. obtained resistance, their growth rate often decreases 4). Typical enzymes that degrade antimicrobial drugs because of protein defects that contribute to their to inactive them include β-lactamase, whereas effective proliferation and the production of many pro- enzymes that modify antimicrobial drugs to inactivate teins unnecessary for their survival; consequently, them include aminoglycoside-modifying enzymes they are weak members of the bacterial flora in the (acetyltransferases, adenylation enzymes, and kinas- struggle for existence and thus will normally die out es). Mutation in targets to be acted on include: methy- naturally. However, adding antimicrobial drugs to the lation of ribosomes, which are targets of macrolide environment kills drug-sensitive bacteria, resulting in antimicrobials; mutations in the 23S rRNA domain V the survival of the antimicrobial drug-resistant bacte- of 50S ribosomes; and mutations in DNA gyrases or ria, which used to be the weaker strains (antibiotic topoisomerase IV, which are targets of quinolone selective pressure) (Fig. 3). antimicrobials. Mechanisms of resistance that decrease Drug-resistant bacteria often die out when exposed the concentration of antimicrobial drugs in bacteria to antimicrobial drugs at a higher concentration than include the inhibition of influx because of the reduction that which kills drug-sensitive bacteria. However, a or defect of porins (which play a role in nutrient intake drug concentration between that which can inhibit the in the outer membrane proteins); such porins are growth of drug-sensitive bacteria and that which can responsible for the permeability of antimicrobial drugs

Antibiotic-resistant Antibiotic High number of bacteria Antibiotic kills susceptible The resistant strain proliferates with a subset of antibiotic- strains; the resistant strain without competition. resistant organism. survives.

Fig. 3 Effect of selective antibiotic pressure in bacteria

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Pumping out Table 1 WHO Priority pathogens list (increasing active Inactivation efflux of the drugs) (modified or degraded the drugs) Priority 1: CRITICAL antimicrobial Acinetobacter baumannii carbapenem-resistant Pseudomonas aeruginosa carbapenem-resistant carbapenem-resistant Enterobacteriaceae 3rd generation cephalosporin-resistant

Priority 2: HIGH Enterococcus faecium vancomycin-resistant methicillin-resistant Staphylococcus aureus vancomycin intermediate and resistant Impermeability Modification (modified cell wall protein) (modified drug targets) Helicobacter pylori clarithromycin-resistant Campylobacter fluoroquinolone-resistant Fig. 4 Mechanisms of antimicrobial resistance Salmonella spp. fluoroquinolone-resistant 3rd generation cephalosporin-resistant Neisseria gonorrhoeae and can overexpress drug efflux pumps, thus facilitate fluoroquinolone-resistant transporting the drugs out of the bacteria. Priority 3: MEDIUM Obtaining more than one mechanism of resistance to Streptococcus pneumoniae penicillin-non-susceptible antimicrobial drugs in the same category causes high- Haemophilus influenzae ampicillin-resistant level resistance whereas obtaining mechanisms of Shigella spp. fluoroquinolone-resistant resistance to more than one antimicrobial drug causes multidrug resistance; these situations cause difficulties with treatment in clinical settings. superbug” by the Centers for Disease Control and Pre- vention (CDC); carbapenem-resistant Acinetobacter 3. Antimicrobial Drug-Resistant Bacteria that baumannii; and carbapenem-resistant Pseudomonas Urgently Require the Development of New aeruginosa. Carbapenems, including meropenem, are Antimicrobial Drugs drug of last resort in the treatment of bacterial infec- On February 27, 2017, the World Health Organiza- tions because they display a broad antimicrobial spec- tion (WHO) announced 12 antimicrobial drug-resistant trum covering gram-positive bacteria, gram-negative bacteria that were highly likely to threaten human bacteria, and anaerobic bacteria; thus, resistance to health from a public health perspective and for which carbapenem is a serious problem. Simultaneously, the development of new antimicrobial drugs was because these drug-resistant bacteria are often resist- urgently required. These 12 pathogens were identified ant to other antimicrobials (multidrug resistance), dif- from a list of antimicrobial drug-resistant bacteria ficult cases to treat occur one after another. against which antimicrobial drugs generally used in the The major factors of resistant to carbapenem include clinical setting were no longer effective4) (Table 1). inactivation in which β-lactamase (carbapenemase) This was the first time that the WHO has announced hydrolyzes carbapenems; carbapenemases owned by such a list. Acinetobacter baumannii, Pseudomonas aeruginosa, and The category of “critical”, which indicates the most Enterobacteriaceae, that are categorized as “critical” in urgent, includes three bacteria: carbapenem-resistant the WHO’s list, degrade most β-lactams, such as car- Enterobacteriaceae, which was named a “nightmare bapenems (Table 2).

Table 2 β-Lactamase classification

Class Typical enzyme Active center Substrate specificity

A KPC, ESBLs Serine Penicillins (→ cephalosporines, carbapenems) C AmpC, CMY Serine Cephalosporins (→ penicillins, carbapenems) D OXAs Serine Oxacillins (→ penicillins, carbapenems) B NDM, VIM, IMP Metallo (Zn) All β-lactams (except monobactams) Red: Carbapenemases

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Environmental Changes Related to the of antimicrobial drugs. Because the issues of clinical Development of Drugs for the Treatment of studies and profitability cannot be resolved through the Infections Caused by Antimicrobial Drug- efforts of pharmaceutical companies alone, govern- Resistant Bacteria ments must take measures to incentivize companies that develop drugs for the treatment of infections 1. World Movement caused by antimicrobial drug-resistant bacteria. For In 2015, the WHO announced the “Global Action example, the Generating Antibiotic Incentives Now Act Plan on Antimicrobial Resistance”,5) which includes of 2011 came into force in the United States with the “increase investment in new medicines”. To meet the aim of promoting drug discovery through incentives, WHO’s demand, Japan established the Ministerial including: [1] designation of innovative drugs for the Meeting on Measures on Emerging Infectious Dis- treatment of infections, [2] priority review, [3] expedit- eases in 2015 and announced the “National Action Plan ed approval and fast track system, and [4] extension of on Antimicrobial Resistance” in April 2016; likewise, patent exclusivity period by 5 years. Furthermore, to the “G7 Ise-Shima Leaders’ Declaration” announced in effectively conduct clinical studies, discussion has been the G7 Ise-Shima Summit in May 2016 a plan that continued regarding convergence in clinical protocols included the “promote research and development of and regulatory requirements under the cooperation novel methods for treatment”. between three regulatory authorities: the Pharmaceu- The Infectious Diseases Society of America issued ticals and Medical Devices Agency, the European Med- messages of “Bad bugs, No Drugs” and “The 10 × ’20 icines Agency, and the FDA. Initiative” in 2004 and 2010, respectively, and actively Expected profits are necessary for pharmaceutical lobbied Congress, with a policy including the develop- companies to energetically engage in research and ment of 10 antimicrobial drugs that are effective development in the field of bacterial infections, and to against antimicrobial drug-resistant bacteria by 2020.6) achieve this, in addition to the above, the introduction These efforts resulted in an improved review system of new incentive systems has been considered. This in a regulatory authority, the Food and Drug Adminis- includes financial cooperation in the research and tration (FDA), on drugs for the treatment of infections development step before approval, called push incen- caused by antimicrobial drug-resistant bacteria. The tives; a system to ensure profitability for companies Innovative Medicines Initiative in Europe established after approval, called pull incentives; and incentives the “New Drugs for Bad Bugs (ND4BB)” program that are a combination of those incentives. In particular, and has strengthened efforts toward the resolution of pull incentives are rather attractive for companies, and scientific and regulatory problems or managerial the following systems have been considered: payment issues that could be barriers to the development of of a reward based on developing or obtaining approval new antimicrobial drugs in seven projects, including of new drugs for the treatment of infections caused by COMBACTE (Combatting Antibiotic Resistance in antimicrobial drug-resistant bacteria (market entry Europe) and ENABLE (European Gram Negative reward), extension of the exclusivity period for market- AntiBacterial Engine). ing in-house, non-antimicrobial products with the high- National measures now support efforts to avoid est profitability (transferable exclusivity), and having running out of countermeasures against antimicrobial public organizations store and purchase the new drugs drug-resistant bacteria, resulting in the significant for the treatment of infections caused by antimicrobial understanding of this as a common problem to all drug-resistant bacteria. humankind. 3. Sustainable Measures against AMR 2. Issues and Measures A bacterium may accidentally own a gene that pro- The major factors blocking in the way of the tects it from antimicrobial drugs and will vertically research and development of new antimicrobial drugs transmit this resistant gene to its descendant. More- are the difficulty of searching for “seeds” of drug dis- over, this gene can also be horizontally transmitted to covery, the difficulty in conducting clinical studies on nearby bacteria. The spread of the drug resistance in drugs for the treatment of infections caused by antimi- this way is an unavoidable natural phenomenon. crobial drug-resistant bacteria, and the low profitability Because the selective risk of antimicrobial drug

SUMITOMO KAGAKU (English Edition) 2019, Report 5 Copyright © 2019 Sumitomo Chemical Co., Ltd. 5 Current Situation Regarding Infections Caused by Bacteria, with Antimicrobial Resistance (AMR) and KS-Project together with the Kitasato Institute Covered by the Cyclic Innovation for Clinical Empowerment (CiCLE) resistance increases in association with the amount of mental improvement for them in order that basic-to- antimicrobial drug use, such drugs should be properly practical research and development in the field of med- used, considering the benefits such as curing an infec- ical care will be conducted continuously and their out- tion and the risks such as the selection of resistant bac- comes will be put to practical use smoothly”. As one of teria. This differs from anticancer drugs that would be the AMED’s measures, a new project called CiCLE used for a long term or drugs for chronic diseases, took off, using 55 billion yen from the supplementary including hypertension, hyperlipidemia, and diabetes budget, and invited applications for the first term in mellitus. It is difficult for pharmaceutical companies to April 2017. CiCLE is a long-term, large-scale project at take on the responsibility of discovering new antimicro- a cost of 0.1 to 10 billion yen for up to 10 years with the bial drugs that are important for global health by their aim of sponsoring research and development for the own abilities under current rules in the circumstance practical application of pharmaceuticals, medical that there is a risk for a shortened drug lifetime devices, regenerative medicine products, and medical because of the emergence and spread of antimicrobial technologies by various types of combinations between drug-resistant bacteria, the amount of use is small companies, universities/colleges, and other organiza- because of use restrictions to prevent the emergence tions, such as collaboration between industry and aca- of antimicrobial drug-resistant bacteria, and an ultra- demia or between industries. CiCLE adopts a system of high drug price would not be approved. sharing risks between the AMED and companies, To take sustainable measures against antimicrobial using the following scheme: milestones and goals of drug-resistant bacteria from the point of view of the the project should be set together with the AMED, and development of new antimicrobial drugs, an idea, the expenses for research and development commis- called “de-linking from sales”, which means de-linking sion should be returned if the goals have been the amount of use (sales amount) of antimicrobial achieved; otherwise, 10% of the expenses should be drugs from the pharmaceutical company’s profit due to returned. the sales amount, is important. For example, the avia- tion industry, which was affected by the spread of infec- 2. KS-Project tion due to a novel influenza virus in 2009, has recog- Based on the importance of the global problem of nized that countermeasures against infections are antimicrobial drug-resistant bacteria mentioned above, important. An idea utilizing new links between values our company believed that the CiCLE project was a has arisen; that is, using the international solidarity good opportunity for conducting discovery research on levy that would be imposed to international airline tick- new drugs for the treatment of infections caused by ets as the resource for measures for infections. Fur- antimicrobial drug-resistant bacteria. Thus, we applied thermore, the realization of some measures that would for CiCLE with a research project entitled “Drug dis- change conventional concepts of pharmaceuticals are covery research aiming at development of agents being considered: for example, changing the recogni- against infections with bacteria showing antimicrobial tion of antimicrobial drugs from “a commodity to pur- resistance (AMR)” jointly with Satoshi Omura, Distin- chase” to “infrastructure shared by the people” and guished Emeritus Professor, Kitasato Institute, who is imposing a charge on prescriptions or a license fee on one of the top researchers on infections in Japanese the use of antimicrobial drugs, just like computer soft- academia; and Hideaki Hanaki, Director of the Infec- ware. tion Control Research Center, and Toshiaki Sunazuka, Professor, Laboratory of Bioorganic Chemistry, both of Project with the Kitasato Institute Utilizing the whom were members of a drug discovery group led by Collaboration of Industry, Academia, and Satoshi Omura. This survived the AMED’s review Government admirably and was selected as one of the seven projects adopted from 48 application titles on July 2017. We 1. Cyclic Innovation for Clinical Empowerment named the joint research on the discovery of drugs for The AMED was established in April 2015 with the the treatment of infections caused by antimicrobial aim “to support research conducted by universities/ drug-resistant bacteria by Omura’s drug discovery colleges, research institutes, and other organizations, group and our company utilizing CiCLE, as the KS-Pro- and address research and development and environ- ject (Kitasato-Sumitomo Dainippon Antimicrobial

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Resistance [AMR] Drug Discovery Project). We began researchers, including us (Hidaka and Takemoto), a full-scale project in October 2017. were dispatched from our company to the Kitasato Satoshi Omura, Distinguished Emeritus Professor, Institute to organize a combined team with researchers was awarded the Nobel Prize in Physiology or Medi- from the Kitasato Institute, and the project is promoted cine in 2015, with Dr. William Campbell who was work- under the overall research support of our company. ing at Merck, “for their discoveries concerning a novel Furthermore, the AMED instructs us through the therapy against infections caused by roundworm para- CiCLE project; therefore, the project is a very open- sites”. The outcome of the research, “ivermectin”, a innovation drug discovery research study operated by drug that treats a parasitic disease, has been used by “all of Japan”, including industry, academia, and the 300 million people annually worldwide and is a specific government. medicine that relieves patients in Africa and Central and South America from fear of blindness. Omura’s Conclusion drug discovery group invented a new separation method for useful microorganisms and has discovered Since the discovery of penicillin, there has been a 42 new species, including 13 new genera. Furthermore, spiral of development of new antimicrobial drugs and the group has established a new search system to iden- the emergence of antimicrobial drug-resistant bacteria. tify bioactive organic compounds from isolated soil bac- Unfortunately, the development of new antimicrobial terium containing the microorganisms and has discov- drugs that are effective against antimicrobial drug- ered over 470 new substances that interest us for both resistant bacteria has currently been a global exigency their structural and bioactive properties.7) Among in which many pharmaceutical companies have with- these substances, 26 natural substances or their deriv- drawn. We strongly believe that providing innovative atives have already been put to practical use as phar- drugs from this project is a responsibility of our com- maceuticals, veterinary drugs, agrochemicals, and pany, which has achievements in the research and reagents for studies. development of antimicrobial drugs; this will help We are expecting significant improvement in the achieve the “National Action Plan on Antimicrobial probability of successful research and development of Resistance” in Japan, improve global health, and con- new drugs with high-level difficulty for the treatment tribute to preventing economic loss. of infections caused by antimicrobial drug-resistant bacteria by bringing together strengths from Omura’s References drug discovery group in the Kitasato Institute, which has the tradition and achievements to launch more 1) J. O’Neill, “Antimicrobial Resistance: Tackling a than one drug for the treatment of infections, and our crisis for the health and wealth of nations. Review company, which has achievements in the research and on Antimicrobial Resistance” (2014). development of antimicrobial drugs and the know-how 2) M. Yagisawa et al., The JAPANESE JOURNAL of a pharmaceutical company. The details of the project FOR HISTORY OF PHARMACY, 50(2), 119 are undisclosed; however, we are aiming to create (2015). drugs for the treatment of infections caused by antimi- 3) G. H. Talbot et al., Clin. Infect. Dis., ciz089, crobial drug-resistant bacteria that break conventional https://doi.org/10.1093/cid/ciz089 (2019), (Ref. concepts and put them to practical use within 10 years. 2019/3/28). We are progressing to reach this goal from several dif- 4) WHO, “Global priority list of antibiotic-resistant ferent angles including the “effect on the mechanism bacteria to guide research, discovery, and devel- of resistance”, “inhibition of the mechanism of infection opment of new antibiotics” (2017). and pathogenic factors”, “restoration of immune sys- 5) WHO, “Global action plan on antimicrobial resist- tem of the host”, and the “physical elimination of path- ance” (2015). ogenic bacteria”. Satoshi Omura, Distinguished Emer- 6) Infectious Diseases Society of America, Clin. Infect. itus Professor, is responsible for the overall supervision Dis., 50, 1081 (2010). as the special coordinator of the project. Several 7) S. Omura, Tetrahedron, 67, 6420 (2011).

SUMITOMO KAGAKU (English Edition) 2019, Report 5 Copyright © 2019 Sumitomo Chemical Co., Ltd. 7 Current Situation Regarding Infections Caused by Bacteria, with Antimicrobial Resistance (AMR) and KS-Project together with the Kitasato Institute Covered by the Cyclic Innovation for Clinical Empowerment (CiCLE)

PROFILE

Jun HIDAKA Isao SHIMIZU Sumitomo Dainippon Pharma Co., Ltd. Sumitomo Dainippon Pharma Co., Ltd. External Innovation External Innovation Project Leader, Fellow, Kitasato-Sumitomo Senior Director, Ph.D. Collaboration

Koji TAKEMOTO Sumitomo Dainippon Pharma Co., Ltd. External Innovation Associate Fellow, Ph.D.

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