SUMMARY STATEMENT 

PROGRAM CONTACT: ( Privileged Communication ) Release Date: 11/01/2016 

Revised Date: 

Application Number: 2 R01 AI042783-16A1 

Principal Investigator 

MUIR, TOM 

Applicant Organization: PRINCETON UNIVERSITY 

Review Group: SBCB 

Synthetic and Biological Chemistry B Study Section 

Meeting Date: 10/19/2016 RFA/PA: PA16-160 

Council: JAN 2017 PCC: M38A 

Requested Start: 04/01/2017 

Project Title: Peptide Autoinducers of Staphylococcal Pathogenicity

SRG Action: Impact Score: 

Next Steps: Visithttp://grants.nih.gov/grants/next_steps.htm 

Human Subjects: 10-No human subjects involved 

Animal Subjects: 10-No live vertebrate animals involved for competing appl. 

Project 

Year 

16 

17 

18 

19 

20 

Direct Costs 

Requested 

Estimated 

Total Cost 

TOTAL 

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section. 

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2 R01 AI042783-16A1 2 SBCB 

MUIR, T 

2R01AI042783-16A1 Muir, Tom 

BIOHAZARD COMMENT 

COMMITTEE BUDGET RECOMMENDATIONS 

Vertebrate Animals 

ADMINISTRATIVE NOTE 

RESUME AND SUMMARY OF DISCUSSION: This resubmission of a renewal proposes to provide 

fundamental insights into how a quorum sensing (QS) system such as the accessory gene regulator 

(agr) operates at the molecular level, and lay the foundation for the development of new strategies for 

treating S. aureus infections. The reviewers are extremely enthusiastic about all aspects of this 

application. Significance is exceptional, as what is discovered in this work will likely translate to other 

Gram+ pathogens. The response to the previous critiques is strong, with the previous animal studies 

removed (although the section describing vertebrate animals was apparently left in by mistake). That 

aim is replaced by innovative new experiments to identify pharmacological modulators. The 

investigative team and environment are unparalleled and this team has discovered much of what is 

known in this field. The rigor of the approach is extremely high, as both unbiased and targeted activities 

are proposed, and alternatives are provided for most experiments. Innovation permeates all of the 

methods and assays. There is a good mix of established techniques and new technologies. The panel 

found no weaknesses worth mentioning and had the highest enthusiasm for the potential impact of this 

application on understanding the S. aureus agr system and its potential application to various bacterial 

pathogens. 

DESCRIPTION (provided by applicant): A research program will be undertaken to study agr signal 

transduction in the commensal pathogen, Staphylococcus aureus. The accessory gene regulator (agr) 

locus found in all staphylococci encodes a quorum sensing (QS) circuit that controls the expression of 

virulence and other accessory genes. It consists of two oppositely oriented transcriptional units, of 

which one encodes four proteins, AgrBDCA, involved in production and sensing of an autoinducer 

peptide (AIP), and the other encodes a regulatory RNA that is the effector of target gene regulation. 

The finding that staphylococcal virulence can be inhibited through antagonism of this QS pathway has 

fueled tremendous interest in understanding the detailed mechanisms at play throughout the circuit. 

Building on recent breakthroughs that have allowed us to reconstitute much as the quorum sensing 

circuit using purified components, we propose to integrate chemical, biochemical, biophysical and 

genetic tools for the purpose of obtaining a deeper understanding into the molecular processes 

underlying the production and sensing of the autoinducer peptide (AIP) pheromone that is central to agr 

regulation. The program will move forward in three directions: Aim 1, identifying the key missing players 

in AIP biosynthesis; Aim 2, understanding how agonism and antagonism of the QS system relates to 

newly discovered conformational changes in the AIP receptor, AgrC, and; Aim 3, identifying novel 

modulators of agr through sophisticated target-based screens. These studies will lay the groundwork 

for the development of therapeutic strategies targeting agr, but also contribute to a fundamental 

understanding of QS systems of this type, which are pervasive in the low-GC bacterial phylum, 

Firmicutes. 

PUBLIC HEALTH RELEVANCE: Staphylococcus aureus (S. aureus) is an opportunistic pathogen 

capable of invading mucous membranes or soft tissue; once invasion occurs, the bacterium deploys a 

diverse arsenal of virulence factors to evade the host immune system and to facilitate spread of the 

infection in the host environment. A research program will be undertaken to study the central quorum 

sensing (QS) circuit, termed agr, which regulates the onset of virulence as a function of bacterial 

population size. Building on recent breakthroughs that have allowed us to reconstitute much of the 

circuit using purified components, we propose to integrate chemical, biochemical, biophysical and 

genetic tools to gain a deeper understanding into the molecular processes underlying agr regulation; 

these studies will provide fundamental insights into how a QS circuit such as agr operates at the 
 

 

 

 

 

 

 

2 R01 AI042783-16A1 3 SBCB 

MUIR, T 

molecular level and will lay the foundation for the development of new strategies for treating 

Staphylococcus aureus infections. 

CRITIQUE 1: 

Significance: 1 

Investigator(s): 1 

Innovation: 2 

Approach: 3 

Environment: 1 

Overall Impact: This is an extraordinary proposal from an experienced world leader in peptide 

chemistry. Along with the co-I, the PI has shaped our current molecular-level understanding of how the 

S. aureus Agr quorum sensing (QS) pathway functions. The proposal not only takes an innovative and 

thoughtful approach to addressing the issue of drug-resistant bacterial infections, but also outlines a 

rigorous approach to revealing certain aspects of the Agr system that have been elusive. A multitude of 

biophysical, biochemical, and synthetic approaches address these current gaps in our comprehension 

of the Agr pathway. The methods are well described, well supported with preliminary data, and 

significant evidence is presented that the investigators will be successful. There are very few 

weaknesses in this resubmitted proposal; the previous reviewer concerns have been adequately 

addressed, and this reviewer is most enthusiastic. 

1. Significance: 

Strengths 

 Antibiotic resistant bacterial infections are becoming rampant and increasingly untreatable, and 

although there are many drugs to treat Gram-positive infections, S. aureus kills more humans 

today than any other bacterium besides M. tuberculosis (MAJOR). 

 It has been noted that the virulence of S. aureus can be altered by disturbing the Agr QS 

pathway; however, there are no medicinal interventions yet available; this proposal would lay 

significant foundational work (MAJOR). 

 There remain critical unanswered questions regarding the Agr system, such as some missing 

players and the consequences of recently discovered receptor conformational changes; this 

serves as the premise of the proposal (MAJOR). 

 Lessons learned on the S. aureus Agr system will most likely transfer to other notorious 

Firmicutes pathogens, such as those from the Streptococcus, Bacillus, Listeria, and 

Enterococcus genera (MAJOR). 

Weaknesses 

 None noted. 

2. Investigator(s): 

Strengths 

 The PI is a recognized leader in chemical biology (MAJOR). 

 The PI has considerable experience in the synthesis of proteins and has developed new 

methods to do so (MAJOR). 

 The PI has been working on the Agr QS pathway for a while and is intimately familiar with it 

(MODERATE). 
 

 

 

 

 

 

 

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MUIR, T 

 Co-I Novick is also a recognized leader in molecular pathogenesis, especially S. aureus, which 

is pertinent to this proposal given that he provides complementary expertise to the PI (MAJOR). 

 Co-I Novick actually discovered the Agr QS pathway (MAJOR). 

 Since 1999, the PI and Co-I have published no fewer than 14 papers together on the S. aureus 

Agr QS pathway. The majority of these papers appear in highly respected, multidisciplinary 

journals (MAJOR). 

Weaknesses 

 None noted. 

3. Innovation: 

Strengths 

 Although Agr QS inhibitors have been known for a while (and some even described by the PI 

and Co-I, e.g., Lyon et al., PNAS, 97,13330, 2000), no global, small-molecule activators of Agr 

QS have been developed (which would be expected to disrupt biofilm formation)(MAJOR). 

 A unique blend of chemical biology approaches is used to identify the proteases responsible for 

AgrD processing (MODERATE). 

 The assay described in figure 6c is quite clever and will be informative if successful(MAJOR). 

 The peptide synthetic methods described in Aim 3.2 are also perceived as a new innovation 

(MODERATE). 

Weaknesses 

 Contrary to what is claimed in the innovation statement, there already have been small molecule 

inhibitors of S. aureus virulence. These compounds block biosynthesis of staphyloxanthin, an 

antioxidant pigment that shields S. aureus from ROS produced by the immune system (see 

PMCID: PMC2747771) (MINOR). 

4. Approach: 

Strengths 

 The experimental approach in all aims is well articulated, thoughtfully designed, and rigorous 

(MAJOR). 

 The investigators have amassed a large amount of preliminary data that supports the majority of 

the proposed work. This lowers the overall risk of the project (MAJOR). 

 The approach overall is rigorous, with proper controls described, alternative explanations given, 

and contingency plans nicely outlined (MAJOR). 

Weaknesses 

 Part of Aim 2.1 proposes to solve the X-ray structure of an integral membrane protein,ArgC. 

The PI states several homologs have been purified and are active. Without a crystal or 

diffraction data, there are serious doubts whether this line of experimentation (solving the 

transmembrane regions) will be successful (MODERATE). 

5. Environment: 

Strengths 

 The environment at Princeton is ideal to carry out the proposed work (MAJOR). 
 

 

 

 

 

 

 

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MUIR, T 

Weaknesses 

 The PI recently moved from NYC to Princeton. The Co-I is still in NYC. The loss of proximity has 

the potential to slow down this highly fruitful collaboration (MINOR). 

Protections for Human Subjects: 

Not Applicable (No Human Subjects) 

Vertebrate Animals: 

Not Applicable (No Vertebrate Animals) 

 Animal studies are not proposed in this revised A1 application, although some vertebrate 

documentation is included. This may have been accidentally included since the A0 application 

did propose animal work (Unacceptable). 

Biohazards: 

Unacceptable 

 This proposal involves the use of pathogenic bacteria; biosafety procedures are not explicitly 

described. That said, the PI and co-I clearly have experience working with thesehazards. 

Resubmission: 

 Aims I and II were received favorably, with concerns mostly pertaining to Aim III. Here, the 

animal studies were deemed premature. The replacement of those experiments with attempts to 

identify a global Agr QS activator are innovative and interesting. 

 The Introduction to Application adequately addresses all other concerns previously raised by 

reviewers. 

Renewal: 

 The PI was fairly productive during the previous grant period, as evidenced by five publications 

found using NIH Reporter (Plasmid 2012, Mol Cell 2014, Chembiochem 2015, PNAS 2015, and 

Cell Chem Biol 2016). Several of these papers detail significant advances for the field. 

Authentication of Key Biological and/or Chemical Resources: 

Unacceptable 

 None are given, nor a justification. 

Budget and Period of Support: 

Recommended budget modifications or possible overlap identified: 

 Money is requested for animal work but animal work is not proposed. 

CRITIQUE 2: 
2 R01 AI042783-16A1 6 SBCB 

MUIR, T 

 

Significance: 1 

Investigator(s): 1 

Innovation: 2 

Approach: 1 

Environment: 1 

Overall Impact: This proposal outlines studies to explore how the virulence-associated quorum 

sensing cascade, agr, is regulated at the molecular level through a series of interesting and wellreasoned experiments. Of particular significance is the role of this circuit in Staphylococcus aureus 

virulence, which can be attenuated by inhibition of the pathway. The PIs have longstanding expertise in 

the study of this pathway and as such, have acquired substantial preliminary data to provide strong 

premise for the proposed studies. The productivity during the previous grant period is good. Scoredriving factors include the strong significance of the proposed work and compelling evidence for each of 

the stated aims (strong premise). The PI adequately addressed the previous reviews and removed 

animal studies, which were thought to be premature. 

1. Significance: 

Strengths 

 

 

 

 

 Staphylococcus aureus is an opportunistic pathogen that causes a large number of infections 

each year, with increasing concern caused by drug-resistant strains. (moderate) 

 Detailed examination of secretion and proteolytic processing of the AIP will yield critical 

information about the mechanisms of these processes, confirm the roles of each actor and 

potentially indicate new targets for therapeutic intervention with a focus on antivirulence 

strategies. (major) 

 Characterization of the sensory domains of histidine kinases is notoriously difficult and the 

devised studies are likely to yield critical information about this feature of ArgC. This will yield 

important information about AIP binding and also provide one of only a limited number of 

examples of the structural characterization of stimuli-HK interactions. (major) 

 The preliminary data provide strong premise for the proposed studies. (major) 

Weaknesses 

 None noted. 

2. Investigator(s): 

Strengths 

 The PIs are accomplished investigators with a longtime collaboration to study S. aureus quorum 

sensing and the agr system. They have complementary expertise, enabling in-depth studies 

such as those in this application. 

 Productivity in the past grant period was good. 

Weaknesses 

 None noted. 

3. Innovation: 

Strengths 
 

 

 

 

 

 

 

2 R01 AI042783-16A1 7 SBCB 

MUIR, T 

 Development of a clever strategy for the biosynthesis of AgrD-thiolactone independent of AgrB 

enabled the postulate that an alternative transporter is required for thiolactone secretion. 

(moderate) 

 Use of new technology, such as nanodiscs, to reconstitute a two competent circuit is innovative 

and exciting. (major) 

 Their hypothesis that opposing mechanical motions regulate the kinase activity of AgrC andthe 

proposed methods of study are intriguing. (moderate) 

 Targeting a virulence pathway for potential therapeutic development has the potential to be 

highly efficacious. (minor) 

Weaknesses 

 None noted. 

4. Approach: 

Strengths 

 The investigators presented strategies to ensure an unbiased approach to the proposed studies, 

often including both a method to perform targeted studies, as well as untargeted experiments to 

assure that the success of the proposed work is not unnecessarily affected by existing 

hypotheses (scientific rigor). 

 Studies to identify the protease responsible for degradation of AgrD and secretion of the 

thiolactone are well thought-out and thorough. (major) 

 The proposed studies to examine the mechanism by which membrane receptor ligation 

activates or inhibits intracellular His kinase activity are both exciting and well conceived. 

Enthusiasm is strengthened by strong preliminary data. (major) 

 The proposed strategy to identify global activators of agr, including the chain inversion method, 

are clever and have a high likelihood of providing such compounds. (major) 

Weaknesses 

 None noted. 

5. Environment: 

Strengths 

 Excellent for conducting this multidisciplinary research, which is evident from the prior 

accomplishments of this collaborative team. (major) 

Weaknesses 

 None noted. 

Protections for Human Subjects: 

Not Applicable (No Human Subjects) 

Vertebrate Animals: 

Not Applicable (No Vertebrate Animals) 
 

 

 

 

2 R01 AI042783-16A1 8 SBCB 

MUIR, T 

 Statement is included but no animal work is proposed in the Research Strategy section. 

Biohazards: 

Unacceptable 

 Biosafety considerations are not discussed although use of pathogens is proposed. 

Resubmission: 

 The PI addressed the previous comments and provided additional preliminary data to support 

this resubmission and address previous concerns about feasibility. 

 Animal studies were removed as recommended and replaced with experiments to furtherdetail 

the interactions on a molecular level. 

Renewal: 

 Productivity is good as judged from publications (5 were noted), several of which were highly 

impactful. 

Authentication of Key Biological and/or Chemical Resources: 

Unacceptable 

 not included 

Budget and Period of Support: 

Recommended budget modifications or possible overlap identified: 

• Funds for animal’s studies should be removed given that these experiments are no longer 

proposed. 

CRITIQUE 3: 

Significance: 1 

Investigator(s): 1 

Innovation: 1 

Approach: 1 

Environment: 1 

Overall Impact: This renewal is a tour de force by an exceptional research team (Muir/Novick) that 

focuses on elucidating the molecular mechanisms underlying agr signal transduction in Staphylococcus 

aureus, a human pathogen that can infect any organ and is responsible for thousands of communityand hospital-acquired infections in the United States alone. The questions being addressed in this 

proposal are highly significant not only because this system is important for S. aureus virulence and the 

work may provide new approaches to prevent and treat infection, but also because of the fascinating 

chemical and biological questions that are being tackled. Innovation is present throughout the proposal 

as evidenced by the questions being addressed and methods being utilized, and both 

hypothesis/candidate-driven approaches and unbiased approaches are presented for many 
 

 

 

 

 

 

 

 

 

 

2 R01 AI042783-16A1 9 SBCB 

MUIR, T 

experiments. The scientific rigor is exceptional. The likelihood for success is apparent from the prior 

track record of accomplishments in this area by the research team, productivity in the prior period of 

support, preliminary data supporting the proposed work, and the multifaceted approach. This 

application is a resubmission and the criticisms from the prior review are adequately addressed. 

Overall, enthusiasm for this ambitious and creative proposal is extremely high. 

1. Significance: 

Strengths 

 The scientific premise of the proposal is excellent. There is exceptional justification for the 

proposed studies, and provided (likely) success, important knowledge gaps will be filled. 

 Understanding the agr system at the molecular level is important because it regulates virulence 

in a human pathogen of particular concern, and insights may provide new approaches for 

preventing and treating infection. (major strength) 

 Biochemical and biophysical characterization is likely to provide new paradigms that may have 

broad impact; for instance, a particularly noteworthy idea put forth in this proposal is a 

connection between cellular proteases and quorum sensing. (major strength) 

 Pharmacological modulators of the agr system will inform whether this system is a viabletarget 

for new antibiotic strategies, and both inhibition and activation of this system are considered in 

the context of this proposal. The latter strategy may have utility in preventing biofilm formation, 

which is a complication on medical devices and surfaces. (moderate strength) 

 Identification of small molecule inhibitors as well as activators of the agr quorum sensingsystem 

will overcome issues with thiolactone-based peptides, and provide new tools to the research 

community and potential leads for new therapeutics for non-traditional targets. (moderate 

strength) 

Weaknesses 

 None noted. 

2. Investigator(s): 

Strengths 

• Exceptional research team – Muir and Novick have been collaborating for >15 years and have 

co-published many papers on the S. aureus Agr QS system, indicating that they are enormously 

productive and creative. (major strength) 

 Novick discovered the Agr QS system. (major strength) 

 Muir has all of the needed expertise in chemical biology and method development requiredfor 

the proposed work. (major strength) 

 Collaboration with Prof. Haw Yang (Princeton) for FRET/TIRF experiments will enable 

experiments in Aim 2.1. (moderate strength) 

Weaknesses 

 None noted. 

3. Innovation: 

Strengths 

 Innovation is found in all aspects of this proposal as highlighted by the creative methods, the 

hypotheses, and the approaches being taken to understand the agr system. (majorstrength) 
 

 

 

 

 

 

Strengths 

 

Strengths 

 

2 R01 AI042783-16A1 10 SBCB 

MUIR, T 

 The idea presented in Aim 3 of identifying a global autoinducer peptide (AIP) activator, 

proposed as a new means to block biofilm by S. aureus, is novel. (moderate strength) 

 Use of the reconstituted two-component circuit in mechanistic studies is innovative. (moderate 

strength) 

 The concept of a link between quorum sensing and protein turnover, including the hypothesis 

that a Clp protease or another AAA+ protease degrades AgrDC to provide the thermodynamic 

driving force for AIP production, is novel and intriguing. (moderate strength) 

 Small molecule screens using ArgC reconstituted in nanodiscs is a creative use of nanodisc 

technology that should have broad application to other types of problems/screens. (moderate 

strength) 

 The combination of chemical biology, structural methods, genetic approaches, and screening 

presented in this proposal is unusual and spectacular. (major strength) 

• The balance of hypothesis/candidate-driven and unbiased approaches is arguably an innovative 

aspect of this proposal and keeps the door open for the option that a hypothesis is proven 

incorrect or that a line of reasoning takes experiments in the “wrong” direction. (minor strength) 

Weaknesses 

 None noted. 

4. Approach: 

 The proposed experiments are backed by extensive assay development (including creative 

assays) and preliminary data from the research team; the likelihood of success and new 

findings is extremely high. (major strength) 

 Balance of hypothesis/candidate-driven and unbiased approaches is a strength of the 

Approach. (moderate strength) 

 The combination of methods enables the proposed work and is expected to advance thefield. 

(moderate strength) 

 All of the above strengths contribute to the highly rigorous nature of the proposed work, which 

ensures a robust and unbiased approach. (major strength) 

Weaknesses 

 None noted. 

5. Environment: 

 The environment at Princeton University and NYU for conducting this research at the 

chemistry/biology interface is excellent, as exemplified by all of the prior accomplishments of the 

research team. (major strength) 

Weaknesses 

 None noted. 

Protections for Human Subjects: 
 

 

 

 

 

 

 

 

2 R01 AI042783-16A1 11 SBCB 

MUIR, T 

Not Applicable (No Human Subjects) 

Vertebrate Animals: 

Not Applicable (No Vertebrate Animals) 

 A vertebrate animal section is included (and addresses the four points), but no animal studies 

are proposed in the grant. They are suggested as a line of future work. Of note, animal studies 

were in the original A0 application and in response to the reviewer concerns, these studies were 

removed from the A1 application. 

Biohazards: 

Unacceptable 

 It is noted that BSL2 facilities/approval for Staphylococcus aureus are not explicitly noted in the 

facilities/resources section. Nevertheless, the co-PIs have many years of experience handling 

these organisms. 

Resubmission: 

 The concerns expressed in the critiques of the original submission were thoughtfully and 

convincingly addressed in this revision, and additional preliminary data was included. 

 The greatest reviewer concern seemed to be the animal studies originally proposed in Aim 3. 

The applicant has removed these studies and included new experiments to identify a global Agr 

regulator. 

 The concerns about innovation in the proposal were adequately addressed and the application 

provided a perhaps needed reminder that innovation is found throughout the proposal in terms 

of hypotheses and experimental design. 

Renewal: 

 A publication list was not included in the application, but a literature search indicates the 

research time has been productive and published 5 papers, including work in top journals like 

PNAS and Cell Chem Biol. 

Authentication of Key Biological and/or Chemical Resources: 

Unacceptable 

 Not included. 

Budget and Period of Support: 

Recommended budget modifications or possible overlap identified: 

 Amend budget because animal studies are budgeted for, but not part of the proposed work. 

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO 

SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS’ 

WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: 
 

 

2 R01 AI042783-16A1 12 SBCB 

MUIR, T 

BIOHAZARD COMMENT: Biosafety considerations are not discussed although use of pathogens is 

proposed. 

Vertebrate Animals: While this application is coded for vertebrate animals and a vertebrate animal 

section is included there are no plans described for using vertebrate animals 

COMMITTEE BUDGET RECOMMENDATIONS: 

The budget should be reduced by the amount budgeted for animal studies, since they not part of the 

proposed work. 

ADMINISTRATIVE NOTE: 

Applications submitted for due dates on or after January 25, 2016 are required to include a new PDF 

attachment describing plans for Authentication of Key Biological and/or Chemical Resources that will be 

used in that research study (see NOT-OD-16-011). Reviewers were asked to consider information 

provided in this attachment as part of their evaluation of your application. This attachment was missing 

from your application and could not be assessed. 

Footnotes for 2 R01 AI042783-16A1; PI Name: Muir, Tom 

NIH has modified its policy regarding the receipt of resubmissions (amended applications). 

See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD14-074.html. The impact/priority score is calculated after discussion of an application by 

averaging the overall scores (1-9) given by all voting reviewers on the committee and 

multiplying by 10. The criterion scores are submitted prior to the meeting by the individual 

reviewers assigned to an application, and are not discussed specifically at the review meeting 

or calculated into the overall impact score. Some applications also receive a percentile 

ranking. For details on the review process, see 

http://grants.nih.gov/grants/peer_review_process.htm#scoring.