NEWSLETTER INDONESIA RESEARCH PARTNERSHIP on INFECTIOUS DISEASE July 2018

Issue #58

INA-RESPOND NEWSLETTER INDONESIA RESEARCH PARTNERSHIP ON INFECTIOUS DISEASE July 2018

Requesting Study Data

INDONESIA FOR PUBLICATION DELEGATION VISIT TO PURPOSES

US-NIH The Art of Using Wikipedia for Research

Teixobactin and Odilorhabdins: A New Hope in Antimicrobial Resistance Era

NATIONAL INSTITUTE OF HEALTH RESEARCH AND DEVELOPMENT

INA-RESPONDThe Steering Hermitage Committee Hotel, Meeting A Tribute8-9 August Portfolio 2018 Hotel, The HermitageJakarta Hotel, A Tribute Portfolio Hotel, Photo:Jakarta Dedy Hidayat

2 Issue #58

INA-RESPOND newsletter content

July 2018 Edition | issue #58

EDITOR-IN-CHIEF

M. Karyana EXECUTIVE EDITOR 4 Study Updates Herman Kosasih

CREATIVE DIRECTOR Dedy Hidayat 6 Reports ART DIRECTOR

Antonius Pradana

SENIOR WRITERS 9 Science & Research

Aly Diana, M. Helmi Aziz, Mila Erastuti

REVIEWERS & CONTRIBUTING 14 Comic Corner

MASTHEAD WRITERS

Anandika Pawitri, Dona Arlinda, Dedy Hidayat, Herman Kosasih, Lois E. Bang, Maria Intan, M. Ikhsan FEATURES Jufri, Neneng Aini, Nurhayati

THANK YOU

INA-RESPOND Network & Partners

INA-RESPOND Secretariat

Badan Penelitian dan Pengembangan Kesehatan RI, Gedung 4, Lantai 5. Jl. Percetakan Negara no.29, Jakarta 10560 www.ina-respond.net

By: ANANDIKA PAWITRI, CALEB L. HALIM, LOIS E. BANG, M. IKHSAN JUFRI, VENTY MULIANA SARI

Screening INA102 and Enrolment y 16 July 2018, sites had enrolled B 354 subjects. Sites enrolled 72.6% of screened patients (487 screened patients). Total subjects enrolled based on our enrolment target is 57% (354 from 660). Enrolment progress until 16 July 2018 can be seen in the graphic on the right. Reasons for “Other” Reason There are many reasons why potential subjects cannot be in our study. If the reasons are not included in the inclusion or exclusion criteria, we will put them in ‘other’ category. On the right is the information:

Sites updates Site 510 (Hasan Sadikin Hospital, Bandung) will join us in TRIPOD study in the near future. The complete site team members will be announced soon. Site 600 has joined the study. Dr Hendra Gani Meanwhile, the Secretariat is preparing for the Site Harahap as a new Research Assistant will accompany Preparation Visit. dr Dashari in the study.

4 Issue #58

IV study has been active for six for final document of permission to be signed by the months, and up to 23 July a Hospital Director. Unfortunately, we have not INA104 total of 326 subjects has been received news from site 670 regarding the contract H enrolled (311 adult and 15 with INA-RESPOND. pediatrics subjects). Sites enrolled 70% of screened The aim of INA-RESPOND is to build quality research patients (468 screened patients). Enrolment failure network in Indonesia. That also means we have to reason is mostly because the patients were spread our wings from far west to the far east of represented by their family members when they came Indonesia. Now with the HIV study, we have to the clinic (not by themselves). Two new sites,

collaborated with hospitals in Papua island located in UPDATES STUDY Ansari Saleh Hospital and Persahabatan Hospital, the far east of Indonesia. Next month we will conduct each enrolled one subject last week. Site Assessment Visit to three cities in Papua; Sorong, No new additional site signed contract this month. Jayapura, and Merauke. As for the far west part of Currently, our legal officer is working on extending Indonesia, we have send Collaboration letter with the contract with all 12 sites since all contracts Zainoel Abidin Hospital, Aceh and are still waiting for expired on 15 June. their favourable reply.

This week (23 – 26 July) we are conducting Site Per 23 July, INA-PROACTIVE is implementing protocol Preparation Visit to Site 660 (Wahab Sjahranie Version 2.0. All sites that already have PIMA Analyzer Hospital) in Samarinda. Site 640 (St. Carolus Hospital) may proceed according to the latest protocol version. and Site 650 (Budi Kemuliaan Batam Hospital) are However, sites that do not have the PIMA Analyzer working on the final preparations for site activation. will have to hold the testing until Secretariat send Hopefully, within two weeks these two sites will join them one. Regardless, all active sites will use SDW the study. Site 580 has been granted Local Ethical and CRF Version 2.0. Committee approval for HIV Study and is now waiting

Enrolled Enrolled Site Activation Site Activation Subjects Subjects Site 610 09 Jan Site 570 26 Apr 70 24 (Tangerang Hospital) 2018 (Soetomo Hospital) 2018 Site 630 Site 600 12 Mar 10 Jul 50 (Ansari Saleh Hospi- 1 (Adam Malik Hospital) 2018 2018 tal) Site 550 13 Mar Site 590 18 Jul 53 1 (Wahidin Hospital) 2018 (Sardjito Hospital) 2018 Site 530 3 May (Cipto Mangunkusumo 22 2018 Hospital)

By: HERMAN KOSASIH, M. KARYANA

REPORT

RePORT and CFAR Collaboration culosis (TB) research. TB researchers prognosis, TB pathogenesis, TB Meeting from all countries under RePORT diagnostics, TB treatment response collaborative meeting of consortia were invited, along with and mortality, TB/HIV in pediatrics, the CFAR investigators who have and TB HIV diabetes trisection. At RePORT (Regional Pro- expressed an interest in the poten- the end of the meeting, future re- spective Observational tial of this proposed collaboration search areas of interest were shared Research in Tuberculo- A and in the portfolio of Tuberculosis and partnerships for future cross- sis) and CFAR (Center for AIDS Re- search) was conducted on 2-3 July Research. During this productive consortia collaborations to enhance 2008. The purpose of this meeting meeting, current research portfolios synergy and advance TB/HIV re- were shared, including research on was to understand the resources search were discussed. the epidemiology of TB, biomarkers and gaps in US-NIH funded Tuber- in TB prevention, diagnosis and

6 Issue #58

the team of-the-art features inside this se- from the cure laboratory. National On the third day, Dr Clifford Lane, Institute of the deputy of US-NIAID, head of Mental Clinical Center and our INA- Health RESPOND governing board mem- (NIMH). ber, accepted the delegation. Dur- On the sec- ing the one and half hour meeting, ond day, US Dr Lane explained the structure of -NIAID pre- US-NIH and NIAID in more details. pared a one The discussion was very fruitful and -day tour to boosted the motivation to enhance Frederick the collaboration between the two area, one- institutions Dr Lane also empha- hour drive sized the need for the extension of from NIH the implementation agreement INDONESIAN DELEGATION VISIT main campus, to visit laboratory between US-NIH and Indonesia TO THE US-NIH facilities. The first place was the NIHRD. Before noon, the delegation The Indonesian delegation was led biorepository laboratory where Dr was impressed by how the US-NIH by Dr. dr. Irmansyah, SpKJ. Other Marcia Lara explained in details the Library of Medicine was designed members were Dr. drg. Tati Suryati requirements of the specimens to to protect all the manuscripts from as the head of scientific review be stored in this facility, the proce- threats and by their collections board, NIHRD; dr Muhammad Kar- dures when specimens are received, from all over the world. At the end

yana, MKes as the chair of INA- stored in hundreds of freezers, liq- of the visit, the delegation visited

RESPOND Steering Committee; and uid nitrogen tanks, and walk-in the HIV clinic, and had a very valua- dr Herman Kosasih from INA- freezers with different tempera- ble discussion with DIAIDS and RESPOND scientific division. The tures, and shipped. In the afternoon RePORT team regarding our TRI-

REPORT objectives of the visit that was con- the delegation visited For Detrick, POD and Pro-Active studies. At the ducted from 11-13 July 2018 were the US Army Campus where both end of the trip, Sophia prepare a to obtain information about the NIAID HIV laboratory and Integrat- dinner party to welcome and intro- NIH structure and its clinical re- ed Research Facilities (IRF) are lo- duce the delegation to all the team search facilities, funding and train- cated. In the HIV lab, Robin and Division of Clinical Research (DCR). ing available, and to discuss re- Helena shared their experience Thank you very much to all the DCR search opportunities. regarding HIV assays in their lab, team for your hospitality during our On the first day, Dr Chuen-Yen Lau and offered to assist INA-RESPOND stay. introduced all the integrative facili- reference lab to achieve ties of the clinical center, followed the same standard. At by a meeting with the National the end of the day, the Center for Complementary and delegation visited IRF, Integrative Health (NCCIH) to dis- which is part of the cuss current research conducted by National Interagency NIHRD and NCCIH and the possibil- Biodefense Campus, a ity of future collaboration. Later in group of federal bio- the afternoon, the delegation had a medical research facili- chance to attend how protocols, ties. Here the delega- including the schistosomiasis study, tion was escorted by were reviewed by NIAID scientific Michael Holbrook, the reviewed board. In late afternoon, chief of containment Dr Irmansyah had the opportunity supervisor, and were to discussed and shared ideas with fascinated by the ad- vanced imaging technology and other state-

8 Issue #58 NewsletterINA-RESPOND Requesting Study Data for Publication

By: M. HELMI AZIZ, M. MILA ERASTUTI, and NURHAYATI

ince INA-RESPOND and inform you how to obtain team or network are welcome was established, the our study data for publication. if the SC member from the network has had sev- There are four parties involved involved site granted their ap- S eral studies. Some of in this new SOP: proval. MWC appoints one these studies are on-going, but leader (LMWC) who will be the Manuscript Writing Commit- a couple of them (AFIRE and primary contact during the tee (MWC) Sepsis) have completed their study data request process. enrollment. Like any other The MWC consists of up to 5 MWC is responsible for the study, these studies have valu- members. They may be the development of concept plan, able data/information. Have study’s protocol Principal In- data analysis, writing the first you ever wondered how you vestigator (PI), protocol Co-PI, draft of publication, and publi- can access the data to process investigators, study team cation. it into a publication? members, Steering Committee (SC) members, and designated Approval Committee (AC) This article will summarize our INA-RESPOND secretariat staff The AC is responsible for new Standard Operating Pro- and/or study statistician (if providing review, decision, cedure (SOP) called “Study applicable). In addition, re- reassignment, and withdrawal Data Usage for Publication” searchers outside of the study of the submitted concept plan.

or submit new request for study data usage. DM team will send the requested study data within 10 working days.

After the MWC received the requested study data, the MWC will be responsible for data analysis and publication development within one year after the approval is received. LMWC should ensure the final draft of publication is submitted for approval to the authors and those whose acknowledge prior to the submission to the journal etc.

The MWC must update the publication progress to the AC through the Publication Spe- cialist (PS) designee every 3 months by email to pub- [email protected].

If MWC fails to produce publi- Data Manager (DM) MWC develops the idea to use cation within one year of ap- study data for publication by The DM will provide the re- proval, AC will notify the MWC completing the INA-RESPOND quested data by MWC after AC for reassignment or withdrawal. Concept Plan (CP) and Approv- approves the study data re- al Committee’s (AC) Decision We also developed the Study quest. Form (F-INA-064). Data Usage for Publication – Publication Specialist (PS) Site Guidance to be used by The F-INA-064 form is submit- INA-RESPOND network site The PS is responsible for coor- ted to PS via publikasi@ina- and the document will be dis- dinating the procedure of respond.net for further review tributed within this month. INA study data request until the by the AC. The MWC will get -RESPOND Clinical Research publication. PS will bridge the the final decision from PS with- Site Specialist and Clinical Re- communication between MWC, in 10 working days after sub- search Associate will provide AC, and DM related to study mission. training for this topic either by data usage for publication. If the F-INA-064 form is ap- Teleconference and/or on-site The procedure that needs to be proved by AC, MWC must during site monitoring visits. followed to obtain the desired complete the Data Confidenti- All the forms that are required study data can be seen in Fig- ality Agreement Template (T- to be completed can be found ure1 above. INA-066) and Study Data Us- in INA-RESPOND portal or INA The Investigator and/or study age Request Form (F-INA-065) -RESPOND website (https://ina team within the INA-RESPOND and submit the forms to pub- -respond.net/downloads- network and/or designated INA [email protected] for fur- links/). If you have an idea but -RESPOND secretariat staff ther review by DM team. If the still do not know where to start initiate the formation of MWC F-INA-064 form is approved you can contact us at pub- (max 5 members) and appoint with minor revision or rejected, [email protected] for fur- one leader of MWC (LMWC). the MWC needs to provide ther guidance. revision according to the AC’s comments and repeat the steps

10 Issue #58 NewsletterINA-RESPOND Teixobactin and Odilorhabdins: A New Hope in Antimicrobial Resistance Era

By: M.HELMI AZIZ

SCIENCE & RESEARCH & SCIENCE

ntibiotics are among the most frequently Teixobactin is produced by a species of β- prescribed medications in modern medi- proteobacteria, Eleftheria terrae, genus Aquabacteria. cine. The first antibiotic, Penicillin, was dis- Ling et al. isolate this new compound using iChip tech- covered by Alexander Flemming in 1928, nology (Figure1) which is primarily used to cultivate A (1, 3) and since then, more than a hundred compounds from the “uncultivable” microorganism . The extract from different classes of antibiotics have been introduced iChip cultivation of E. terrae attracts attention since it for medical purposes. By 2050, it is predicted that anti- is inhibiting the growth of Staphylococcus aureus (S. microbial resistance (AMR) will be responsible for aureus) (1, 3, 4). Later, using mass spectrometry, amino more deaths than cancer. The latest class of antibiotic acid analysis, and NMR-spectroscopy, the extract was found in 1987, and despite the rise of AMR, no structure was elucidated, which lead to the discovery new class has been discovered since. due to lack of of Teixobactin (3). pharmaceutical company investment interest. This The relatively high molecular mass (1242 g mol−1) of month article summarizes two breakthrough candi- Teixobactin correlated with its function as antibacterial dates of antibiotic classes, Teixobactin and Odilorhab- properties (3). Teixobactin blocked lipid II dins. (peptidoglycan) and lipid III (teichoic acid) − the bio- Teixobactin synthetic precursor of the bacterial cell wall based on molecule-molecule interaction (3). Although Teixobac- In 2015, Ling et al. published a paper in Nature journal tin has the same mechanism as vancomycin, which about a new class antibiotic called Teixobactin (1, 2). also lipid II binder, it does not show cross-resistance

with Vancomycin (3). Moreover, the in vitro direct com- dins (ODLs), are produced by parison between those two antibiotics showed that Xenorhabdus nematophoila, an ento- Teixobactin has a faster killing profile of S. aureus (3). mopathogenic bacteria that have a However, lipid II and lipid III are abundantly found in mutual relationship with nematodes Gram-positive bacteria, but not in Gram-negative bac- (5). ODLs released by Xenorhabdus teria. This suggests that Teixobactin has little efficacy nematophilia are primarily used to or ineffective to the Gram-negative bacteria, which prevent other competing bacteria and have different cell wall structure (2, 4). fungi invade the insect’s corpse and gave time for the nematode to absorb Related to toxicity, in vitro studies reveal that Teixo- the nutrients from the insect’s corpse bactin showed no adverse effects by showing the ab- during the macromolecular degrada- sence of cytotoxicity, hemolysis, and genotoxicity (3). A tion (5). good half-life in plasma of Teixobactin also has been observed in rodents, dogs, and humans (3). Later, two ODLs are encoded by non-ribosomal studies using a mouse-MRSA-sepsis and Streptococ- peptide synthetases (NRPSs) gene cus pneumonia lung infection models proved that cluster that is present in Xenorhabdus Teixobactin has comparable efficacy with Vancomycin nematophilia. The NRPSs gene cluster and Amoxicillin respectively (3). is well known for its function in Gram- positive actinomycetes as the source Scientists had tried to generate Teixobactin-resistant of antibiotics from the secondary me- mutants’ Gram-positive bacteria but they failed. Re- tabolites (5). Therefore, Lucile et al. sistance to Teixobactin is less likely to develop since it tried to elucidate the secondary me- is targeting lipid molecules, not a protein that is en- tabolite that is produced by Figure 2. Antibiotics that Bind in the Decoding Center on the Small Ribosomal Subunit (A and B). NOSO (Odilorhabdins, yellow) coded by a gene that could mutate and develop re- Xenorhabdus nematophilia and they (STR, cyan), Paromomycin (PAR, salmon), Tetracycline (TET, blue), and Negamycin (NEG, green) sistance. However, Teixobactin is produced in natural found ODLs (5). environment, meaning there are microbes around the environment that are naturally resistant to Teixobactin. Unlike Teixobactin, ODLs are peptide antibiotics that These microbes can transfer the resistance genes to bind with the decoding center of the small subunit of the pathogenic bacteria which similar to the history of the bacterial ribosome (5). This property makes ODLs as Extended-spectrum beta-lactamases (ESBLs) resistant the broad-spectrum antibiotic that is effective for both genes transfer from environmental microbes (2). Gram-positive and Gram-negative bacteria (5). Unlike the other ribosome-targeting antibiotic, ODLs binds to Odilorhabdins at a new site in small ribosomal subunit that is not A new broad-spectrum antibiotic was recently discov- exploited by other antibiotics which makes it excep- ered and published by Lucile et al. earlier this year (5). tional (Figure2) (5). After ODLs bind with the rRNA and This new class peptide antibiotics, called Odilorhab- tRNA, it will stimulate miscoding in the cell-free trans-

Issue #58 SCIENCE & RESEARCH & SCIENCE Figure 2. Antibiotics that Bind in the Decoding Center on the Small Ribosomal Subunit (A and B). NOSO (Odilorhabdins, yellow), Streptomycin (STR, cyan), Paromomycin (PAR, salmon), Tetracycline (TET, blue), and Negamycin (NEG, green) (5).

lation system and protein synthesis (5). without detectable resistance. Nature. 2015;517 (7535):455-9. NOSO-502, the first clinical candidate of ODLs candi- dates, has shown promising results in vitro and in vivo 2. Piddock LJ. Teixobactin, the first of a new class of antibiotics discovered by iChip technology? The Jour- in the mouse model (6, 7). NOSO-502 is active against a nal of antimicrobial chemotherapy. 2015;70(10):2679- panel of Gram-positive and Gram-negative bacteria, 80. including carbapenem-resistant and polymyxin- resistant bacteria in vitro (7). In addition, there was no 3. von Nussbaum F, Sussmuth RD. Multiple attack on cytotoxicity against HepG2, HK-2, or HRPT cells which bacteria by the new antibiotic teixobactin. An- gewandte Chemie (International ed in English). suggested the favourable safety profile of NOSO-502. 2015;54(23):6684-6. The plasma levels of NOSO-502 are stable when tested to mouse, rat, dog, monkey, and human plasma (7). 4. Wright G. Antibiotics: An irresistible newcomer. Na- Moreover, the efficacy was tested in murine infection ture. 2015;517(7535):442-4. models and proven effective against Gram-negative 5. Pantel L, Florin T, Dobosz-Bartoszek M, Racine E, pathogens including Eschericia coli and Klebsiella Sarciaux M, Serri M, et al. Odilorhabdins, Antibacterial pneumoniae (6, 7). Agents that Cause Miscoding by Binding at a New Ribosomal Site. Molecular cell. 2018;70(1):83-94.e7. Two new classes of antibiotics have been discovered in 6. Zhao M, Lepak AJ, Marchillo K, VanHecker J, Andes the past five years, but both antibiotics still need to be DR. In Vivo Pharmacodynamic Characterization of a thoroughly investigated for their therapeutic potential Novel Antibiotic Odilorhabdins, NOSO-502 against and safety profile. The development of new antibiotics Escherichia coli and Klebsiella pneumoniae in a Mu- as the last resort to combat AMR is a critical subject rine Thigh Infection Model. Antimicrobial agents and for healthcare researchers around the world including chemotherapy. 2018. Indonesia. 7. Racine E, Nordmann P, Pantel L, Sarciaux M, Serri M, References Houard J, et al. In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation. 1. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels Antimicrobial agents and chemotherapy. 2018. I, Conlon BP, et al. A new antibiotic kills pathogens

“No Jimmy! You can’t cite Wikipedia as the main source for 14 your assignment!” Issue #58 NewsletterINA-RESPOND The Art of Using Wikipedia for Research

By: ALY DIANA

es, there is a big stamp on Wikipedia which So far, we have come to understand what Wikipedia is says that it is not a credible/reliable source and covered its strengths and weaknesses. We have for academic citation. The unique thing with also talked about how to use Wikipedia wisely for our Y Wikipedia is anyone may edit an article, de- academic research. Considering how Wikipedia is leting accurate information or adding false information widely used and accessed by people around the world – which is one of the many factors Wikipedia can keep to get information, contributing in this massive grow- growing. It provides free knowledge from mostly un- ing source of information and sharing our own exper- paid contributors (as long as you can get an access to tise to create better and more accurate articles is en- internet and proper gadget). However, lack of respon- couraged by more and more universities. Researchers sibilities of the author(s) of a Wiki’s article seems to and scholars can contribute by editing existing entries CORNER COMIC create a substantial amount of doubt to deny its validi- and/or creating new ones. This is actually a good way ty to join other peer-review sources as an academic to share our knowledge and provide sound scientific citation. facts to wider audiences. At the very least, it provides a chance for us to practice. Wikipedia itself provides some useful articles about this particular topic, for example: “Researching with I believe that this is a very simple article with a clear

Wikipedia”, “Wikipedia: Academic Use”, and “Reliability conclusion, regardless the debates out there about of Wikipedia”. Amazingly, increasing number of univer- citing vs. not citing Wikipedia. In addition, if you have sity libraries also provide guides on using, editing, and the time, these useful links may provide you with extra contributing to Wikipedia. Some acknowledge Wikipe- information related to this issue. dia as “one of the largest open educational resources http://guides.library.cornell.edu/wikipedia and http:// in the world”, which is somewhat true. In general, the libguides.library.nuigalway.ie/wikipedia. articles in Wikipedia can help us with our research by gathering background information on a topic, using References: the references to broaden our search on the topic and Cornell University Library. Editing and Contributing to generate search terms that could be used when Wikipedia, http://guides.library.cornell.edu/wikipedia searching the library or a database. The main ad- vantage of reading a Wikipedia article is that it gives a National University of Ireland Galway. Wikipedia - Re- quick access to a lot of information, and the infor- search & Contributing, http:// mation can mostly be digested well because it is writ- libguides.library.nuigalway.ie/wikipedia ten in a colloquial language. Wikipedia: Reflections on Use and Acceptance in Aca- The most important thing when we are reading an demic Environments, http://www.ariadne.ac.uk/ article in Wikipedia (or in any sources, really) is to keep issue69/whalley our critical mind. Nothing can be considered a fact Wikipedia: Wikipedia as a research tool, https:// until it has been confirmed. Starting to gain knowledge libguides.exeter.ac.uk/c.php?g=658259&p=4648406 through Wikipedia, especially on a topic that is beyond our own expertise, is a good practice to maintain and improve our ability in exercising our critical appraisal.

July 2018 Edition INA-RESPOND website: www.ina-respond.net

INA-RESPOND Newsletter The Indonesia Research Partnership on Infectious Disease newsletter is an internal bulletin of INA-RESPOND research network intended to disseminate information related to the network’s studies, activities, and interests to all members of the network as well as its sponsors and related parties. The INA-RESPOND newsletter welcomes all network members and stakeholders to contribute by submitting articles related to the network’s studies and interests. Send your articles or subscribe to our latest newsletter by sending an email to [email protected]