The Gap Between a Discovery and a Drug Program
Academic laboratories remain an important source of antibacterial innovation, but much of the preclinical antibacterial pipeline is carried by academic institutions, micro-sized companies, and small companies rather than organizations with extensive internal drug-development infrastructure.1 That creates a practical challenge when promising discoveries need to make the transition from research projects into programs that another organization can develop and finance.
A compound may demonstrate convincing antibacterial activity while the program around it still lacks a medicinal chemistry strategy, preliminary toxicology, an appropriate efficacy model, a scalable route to material, or a clear idea of the clinical product it is meant to become. An analysis of unsuccessful antibacterial funding applications found recurring weaknesses in hit and lead characterization, differentiation, understanding of toxicological liabilities, resistance assessment, R&D strategy, and the expertise represented on project teams. More specific gaps included limited structure-activity relationship (SAR) knowledge, insufficient medicinal chemistry strategy, weaknesses in animal proof-of-concept studies, inadequate use of pharmacokinetic/pharmacodynamic (PK/PD) principles, and a lack of clear progression criteria.2
These deficiencies illustrate the distance between validating a scientific discovery and assembling a drug development program. As a candidate advances, decisions in chemistry, microbiology, safety, efficacy, formulation, manufacturing, and regulatory strategy increasingly depend on one another. Closing the gap requires translational infrastructure capable of turning a scientific opportunity into a defined product-development plan.
Start With the Product, Not Just the Molecule
One of the earliest steps is determining what the eventual antibiotic is supposed to become. Target product profiles (TPPs) for antibacterial agents can define intended clinical use and target populations along with desired pharmacokinetic characteristics, efficacy, safety, route of administration, stability, access, and affordability.3
Those choices provide a framework for candidate optimization. Antibacterial discovery programs can tie progression criteria to target candidate profiles and TPPs rather than advancing compounds without predetermined standards for what a successful candidate needs to achieve.
Medicinal chemistry is therefore not simply seeking the molecule with the highest antibacterial potency. The program is attempting to produce a candidate whose overall characteristics fit an intended therapeutic use. Pharmacokinetics, safety, administration, stability, and other product attributes can begin shaping decisions while chemistry and preclinical strategy are still evolving.
Medicinal Chemistry Has to Turn Activity into a Candidate
The transition from antibacterial activity to a development candidate places substantial demands on medicinal chemistry. Insufficient SAR understanding and weak medicinal chemistry strategy have been identified as barriers to progression in antibacterial discovery programs, while SAR optimization can require substantial resources and specialized expertise.
As a project matures, medicinal chemistry must operate within a wider development system. Changes intended to improve antibacterial activity need to be considered alongside absorption, distribution, metabolism, and excretion (ADME), safety, microbiological behavior, and the other characteristics required by the target candidate profile. A series that continues to generate active analogues is not necessarily moving closer to a viable drug candidate if critical liabilities remain unresolved.
This is one point at which the transition out of a purely academic discovery environment can become difficult. A research group may have deep expertise in a bacterial target, mechanism, screening platform, or chemical series while lacking some of the adjacent capabilities needed for a complete lead-optimization campaign. The issue is not the quality of the originating science. It is the widening range of decisions that must be made as the project moves toward a drug candidate.
Clear progression criteria help prevent a program from continuing to generate compounds and data without establishing whether the series is approaching a candidate worth developing. Linking medicinal chemistry to defined candidate and product profiles provides a basis for deciding which deficiencies can be optimized, which are incompatible with the intended product, and when additional investment in a series is no longer justified.
De-Risk Candidates Before Capital Requirements Escalate
Lead optimization also needs to expose weaknesses rather than simply generate increasingly positive data sets. Preliminary toxicology, PK/PD, appropriate animal efficacy studies, and resistance characterization all contribute to determining whether an antibacterial candidate has a plausible path forward, and deficiencies in each of these areas have been identified in antibacterial discovery projects.
Safety deserves particular attention because liabilities missed during early discovery can emerge during substantially more advanced development. An analysis of Gram-negative antibiotic programs discontinued between 2010 and 2020 identified the transition between phase I and phase II as a major point of attrition and found that safety issues contributed to discontinuation among the programs examined.4 The finding applies specifically to the Gram-negative candidates included in that analysis, but it underscores the importance of investigating toxicological concerns before a candidate reaches more resource-intensive stages.
PK/PD provides another test of whether promising activity can translate into a plausible therapeutic. In vitro activity alone does not demonstrate that the necessary exposure can be achieved, and PK/PD competence has been identified among the capabilities needed for progressing antibacterial discovery projects.2
Animal proof-of-concept studies can create a separate infrastructure hurdle. Academic programs may lack funding or access to appropriate testing facilities, while poorly selected or nonstandardized models can produce efficacy results that are difficult to interpret. Resistance also requires early attention. Development planning for anti-infectives can include resistance emergence, cross-resistance, mechanism of action, susceptibility testing, and related microbiological questions before an Investigational New Drug (IND) submission.5
The practical aim is to surface important liabilities while they can still influence candidate selection and program design.
Formulation and Manufacturing Cannot Wait Until the IND
A candidate can meet biological criteria and still present a serious translational problem if it cannot be produced, characterized, formulated, and supplied in quantities suitable for continued development.
Scale-up feasibility has been identified as a weakness in some antibacterial discovery programs, including cases in which teams could not readily produce sufficient quantities of highly pure compound for expanded biological profiling. Natural-product programs can face additional problems when fermentation capacity or yield constrains the amount of material available for development studies.
These issues bring chemistry, manufacturing, and controls (CMC) into the program before formal regulatory submission. Early FDA interactions for anti-infective development can address drug substance identity, dosage-form composition, manufacturer, manufacturing process, specifications, analytical methods, and available stability information.5
Formulation is also linked to the product a program intends to create. Route of administration and stability are among the attributes that can be defined within an antibacterial TPP, connecting formulation choices to the intended clinical use of the candidate.
Development readiness at this stage does not require a commercial manufacturing process. It does require enough understanding to answer more immediate questions: Can sufficient material be produced? Can its identity and quality be characterized? Is there a workable dosage form? Are there obvious stability or scale-up problems that could prevent the candidate from advancing?
Leaving all of those questions to a future licensee or investor does not make them disappear. It transfers basic technical uncertainty into the handoff.
Regulatory Strategy Is Part of Experimental Strategy
Regulatory planning can begin well before a submission is assembled. For anti-infectives, the FDA encourages early engagement while product-quality, nonclinical, microbiological, and clinical-development plans can still be influenced.5
The value extends beyond preparing documentation. Early regulatory planning can bring CMC, toxicology and pharmacology, microbiology, resistance, animal models, and clinical-development strategy into the same framework. The proposed clinical plan can also affect the design of nonclinical studies.
Regulatory expertise therefore serves a design function as well as a documentation function. It can help determine what evidence the program will eventually need and whether experiments being planned today will answer questions that later development decisions depend on. Early regulatory input can direct limited resources toward studies that will also support those later decisions.
The Missing Capability May Be the Team Itself
Some translational gaps cannot be corrected simply by commissioning another assay. Evaluations of antibacterial discovery projects have identified deficiencies in overall R&D expertise and structured development planning alongside shortcomings in specific experimental areas.2
A program moving toward development requires decisions across microbiology, medicinal chemistry, ADME and PK, toxicology, efficacy models, formulation, CMC, regulatory strategy, and product objectives. Access to those disciplines matters, but so does the ability to interpret their findings together. An outsourced toxicology, efficacy, or formulation study only advances the broader program when someone can determine what the result means for candidate progression and what should happen next.
Expecting every academic laboratory to recreate the infrastructure of an experienced drug development organization would be unrealistic. A more practical model is to give promising programs access to the expertise and platforms they are missing. Centralized mentorship and accessible drug discovery services have been proposed specifically as ways to address recurring weaknesses in antibacterial projects.2
The asset being handed from academia to a downstream developer is therefore more than a molecule. It is the molecule together with the evidence, strategy, and development logic needed to explain why it should advance.
What Makes a Program Development-Ready?
Development readiness should not imply that an academic program has eliminated preclinical risk or completed work that properly belongs within a venture-backed company. A more useful threshold is whether enough structure and evidence exist for the next organization to understand what is being developed, what has been demonstrated, which major questions remain, and what work needs to happen next.
That begins with product intent and meaningful candidate-progression criteria. The chemical series should have a coherent optimization strategy supported by sufficient SAR, medicinal chemistry, microbiological, and ADME information to explain why particular compounds are advancing. Important liabilities should be investigated through appropriate resistance work, PK/PD, preliminary safety assessment, and fit-for-purpose efficacy studies.
There should also be a plausible path to supplying the candidate. That does not mean establishing commercial manufacturing readiness, but enough should be known about synthesis or production, material quality, analytical characterization, formulation, and stability to support further development.
Finally, these activities need to form a coherent plan rather than a collection of unrelated experiments. At that point, a downstream party can identify why the candidate has progressed, which uncertainties remain, and what further work is required. Development readiness does not prove that the candidate will succeed. It makes the scientific and technical proposition sufficiently defined for another organization to evaluate what it would be financing.
Shared Infrastructure Can Close the Translational Gap
The capabilities required to reach that point do not necessarily have to reside within the originating institution. Several AMR initiatives have developed different models for supplying technical expertise, experimental capacity, development oversight, and connections to later-stage funding around projects that would struggle to assemble those resources independently.
The European Gram-negative Antibacterial Engine (ENABLE) demonstrated one model. It operated as a shared antibacterial drug-discovery and development platform for external programs, bringing together capabilities across chemistry, microbiology, safety, modelling, and other development disciplines.6,7
Across ENABLE, 23 programs were accepted, six reached lead status, three produced development candidates, two entered preclinical studies, and one advanced into phase I.7 The model showed that specialized capabilities could be concentrated in shared infrastructure rather than rebuilt independently around each originating project.
ENABLE-2 builds on lessons from ENABLE with a focus on early antibiotic discovery and development. Its platform combines medicinal chemistry, microbiology, ADME, safety, and in vivo efficacy capabilities with development guidance. Its Hit-to-Lead program can also provide formulation expertise, advice on development strategy and TPPs, and support for approved work performed through external contract research organizations.8,9
Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), a global nonprofit partnership, provides a broader accelerator model that pairs funding with scientific, regulatory, preclinical, and business support. Dedicated support teams can help developers interpret toxicology findings, review regulatory materials, work with outside research providers, and address project-specific development risks.10 Product developers can also access synthesis and manufacturing support and other preclinical services.
The CARB-X Clinical Advisory Board provides a particularly clear example of how these functions can converge early. It works with developers on the intended drug label, the documentation needed for approval, regulatory strategy, and phase I study design, including whether the study will generate information useful to downstream investors. Clinical strategy, experimental design, regulatory planning, and preparation for later financing are therefore addressed within the same support structure rather than as separate sequential steps.
The INCubator for Antimicrobial Therapies in Europe (INCATE) addresses the academic-to-investment transition more explicitly. It brings together basic and translational research, industry expertise, experienced entrepreneurs, and investors to help antimicrobial innovations move toward industrial development and investable ventures. Its model combines advice and non-dilutive support with a focus on resolving the translational and business questions that determine whether a project can credibly take the next step.11,12
Selected INCATE projects can receive up to €250,000 in non-dilutive support to address critical questions needed to construct stronger translational and business plans.12
ENABLE, ENABLE-2, CARB-X, and INCATE differ in structure and in the stages they support. Collectively, they show how shared experimental infrastructure, specialized development expertise, program mentorship, and business-development support can provide capabilities that individual academic groups or young companies cannot always maintain internally.
Building a Better Handoff from Academia to Development
Academic institutions and small organizations carry substantial antibacterial innovation, while the path toward a viable candidate demands expertise across disciplines that may sit outside the originating laboratory. A better handoff begins by recognizing that translation does not require an academic project to resemble a finished pharmaceutical development program. It requires enough of the right questions to be answered for a downstream organization to judge whether the opportunity warrants further development.
Existing shared-infrastructure models show that the necessary capabilities can be supplied through platforms and partnerships that identify promising programs, expose liabilities, fill critical development gaps, and prepare candidates for the organizations that will carry them further.
For antibiotic innovation, that work should begin before a promising discovery is packaged for investors. The goal is not to make every academic finding look investment-ready. It is to build enough development infrastructure around the most promising findings to determine which ones genuinely deserve to become drug programs.
