Key Points

• Antimicrobial Resistance (AMR) is a global health threat predominantly caused by a certain set of bacteria often referred to as the ESKAPE organisms (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter spp.).

• To address AMR, new antibiotics need to be discovered and approved.

• Between the 1940s and 1960s, systematic exploration of microbes yielded multiple new antibiotic families, marking the “Golden Age of Antibiotics”. From the 1970s onward, the discovery of new antibiotic classes slowed dramatically while resistance rose and research efforts declined.

• At the present day, the discovery of new antibiotics is slowed down due to limited revenue to the pharmaceutical industry, which is why new tools that lower costs and feasibility for antibiotic discovery are needed.

Antimicrobial Resistance

Imagine a world, in which a simple cut on your hand or a routine surgery could once again become life-threatening. This is not science-fiction, it is the growing reality of antimicrobial resistance (AMR). Over time, bacteria have learned to outsmart the very drugs designed to defeat them.

Antimicrobial resistance occurs when bacteria evolve mechanisms to survive exposure to antibiotics that would normally kill them or inhibit their growth. As a result, infections become harder to treat, requiring stronger, more specific drugs. According to the World Health Organization (WHO), AMR is one of the top global health threats of the 21st century, projected to cause up to 10 million deaths annually by 2050 if left unaddressed^[1].

In addition, antimicrobial resistance reduces treatment effectiveness and places significant strain on healthcare systems. Infections caused by resistant pathogens often require additional antibiotics, more frequent medical visits, and extended hospital stays, which substantially increase healthcare costs. These costs extend beyond the patient to families, societies, and future generations. By 2050, AMR is expected to reduce global GDP by 1.1–3.8% annually, with low- and middle-income countries most affected due to limited access to diagnostics, effective treatment, and financial resources.^[2].

The ESKAPE Organisms

The main drivers of AMR are the so-called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) (Tab. 1). These organisms “escape” the effects of antibiotics due to multiple resistant mechanisms and are leading causes of hospital-acquired infections worldwide^[3]. This group of pathogens urgently needs to be addressed by new antibiotics, since the occurrence of multi-drug-resistant strains is remarkably alarming in common infections^[4].

Worryingly, resistant strains of some of these organisms are now being detected far beyond hospital walls, in natural environments, water supplies, wastewater, wildlife, and urban settings, giving the acronym ESKAPE an even more concerning meaning^[5].

A Brief History of Antibiotic Research

The message is clear: we need to act now and develop new antibiotics to counter rising resistance. Yet, if the urgency is so apparent, why did the progress and development come to a halt?

To explore this, we looked back at the origins of antibiotic research.

Golden Age of Antibiotics

When Alexander Fleming noticed a strange mold killing his bacterial cultures in 1928, he could hardly imagine how much it would change the world. That mold, Penicillium notatum, gave rise to penicillin, the first true antibiotic^[10]. By the 1940s, penicillin was being mass-produced, and suddenly diseases that had terrorized mankind for centuries like pneumonia, syphilis, septic wounds could be treated with a simple injection. It was like opening a hidden treasure chest.

Scientists turned to nature in search of new antibiotics. Soil samples, fungi, and bacteria became valuable resources, as researchers screened them for compounds with antibacterial activity. This systematic exploration led to the discovery of entirely new antibiotic families such as tetracyclines targeting the 30S ribosomal subunit, macrolides targeting the 50S subunit, and penicillins targeting the bacterial cell wall, initiating the Golden Age of Antibiotics (Fig. 1)^[11].

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The Discovery Void

By the 1970s, the drug discovery lost its momentum. Many scientists realized that the “low-hanging fruits” had already been harvested. Meanwhile, bacteria were evolving. Resistance spread quickly through hospitals, and infections once easily cured became stubborn again. Yet, ironically, at the same time, pharmaceutical companies began to look away. Antibiotics were not seen as profitable anymore: they were short-course treatments, and doctors were encouraged to hold new ones in reserve to prevent excessive selection for resistant strains^[15][16]. This era became known as the “Discovery Void”. It was not a sudden collapse but a quiet fading of momentum^[16].

While discovery slowed, occurrence of resistance advanced, reminding us that innovative strategies are no longer optional but essential.

Hurdles in Drug Approval

Even when a new antibiotic is discovered, the road to patients is long and full of obstacles. Before reaching the market, every candidate must pass through preclinical tests and three phases of clinical trials. This process often takes more than ten years.

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Moreover, unlike drugs for diabetes or hypertension, antibiotics are used for short periods and are often held in reserve to delay the occurrence of potential resistance. From a commercial perspective, this reduces profitability and discourages pharmaceutical companies from investing heavily in antibiotic pipelines. As a result, many large companies have abandoned antibiotic R&D entirely, leaving the field underfunded and dependent on smaller biotech companies and public initiatives^[17][18].

Lastly, many potential drug candidates fail due to toxicity, insufficient efficacy, or delivery issues. Even those that succeed must undergo complex regulatory approval procedures that take 12–18 years on average^[19] (Fig. 2). Over the course of this lengthy process, numerous potential candidates are ruled out for not meeting the rigorous safety standards. As a result, only about 5–12% of new compounds are ultimately approved as drugs, depending on their target^[20].

Where We Stand Today

Despite decades of progress in drug development, the antibiotic pipeline today remains alarmingly empty. Most of the drugs approved in recent years are derivatives of existing classes, offering only minor improvements rather than true breakthroughs^[11][16]. Meanwhile, multidrug-resistant pathogens, especially the ESKAPE organisms, continue to spread, reducing the effectiveness of our limited drug repertoire^[18].

This gap highlights a central problem: traditional discovery methods have reached their limits. Over the past decades, existing compound libraries have been screened extensively, mostly through target-based approaches, where the focus lies on how a compound interacts with a specific protein or molecular structure. In the case of antibiotics, however, this strategy is suboptimal. Barriers such as the bacterial cell wall and the outer membrane of gram-negative bacteria often prevent compounds from reaching their intended targets. As a result, even a molecule that binds effectively to its target may show no antibacterial activity if it cannot enter the cell.

In contrast, phenotypic screening offers a more suitable path for antibiotic discovery. By taking the complexity of the cell into account, phenotypic screening opens the door to truly novel discoveries. Unfortunately, this approach is still rarely used in today’s drug development cycle.

What is urgently needed is greater chemical diversity, exploration of new chemical space, and improved screening strategies to enable the discovery of genuinely novel and effective antibiotic candidates^[16].

To meet this challenge, new discovery paradigms are urgently needed. The world needs bold approaches that combine discovery, design, delivery, and our platform is a crucial step in that direction. With our innovative expression and engineering protocols tailored to NRPS, we open the door to the discovery of new compounds and unexplored chemical space. On top of that, our activity screening strategy focuses on phenotypic screening, a powerful approach particularly well-suited for antibiotics, yet still largely overlooked by today’s pharmaceutical industry.