In the late 1980s, science entered an antibiotic drought. No new classes of these valuable drugs were discovered for over 20 years, only ending with the approval of diarylquinolines in 2011 (1). There’s now cause for slight optimism with the announcement of a new drug class earlier this year — the first antibiotic in 50 years to act against Acinetobacter baumannii, a major source of hospital-acquired infections (2). But these drip-fed discoveries come against the backdrop of a wave of antibiotic resistance. Clinicians are currently fighting against numerous bacterial diseases with last-line options, said Michael Caparon, a microbiologist at Washington University in St. Louis.

Now, Caparon and his colleagues have shown for the first time that a new antibiotic with efficacy against multiple pathogens can slow a deadly bacterial disease. They published their results in the journal Science Advances (3). The team tested their novel compound on a flesh-eating tissue infection in mice caused by the Gram-positive bacteria Streptococcus pyogenes. 

The discovery of this new antibiotic was a mix of innovation and accident. Caparon had been searching for solutions to catheter-linked urinary tract infections caused by Enterococcus faecalis. During these infections, E. faecalis forms a biofilm across the surface of the catheter. Caparon, working in collaboration with fellow microbiologist Scott Hultgren — also of Washington University — and Fredrik Almqvist, a medicinal chemist at Umeå University in Sweden, wanted to target E. faecalis’s pili: small hook-like appendages that the bacterium uses to lock into place onto catheters. 

They’re not only killing the bacteria, but they're inhibiting some of its key virulence factors. 
- Chris LaRock, Emory University

Hultgren and Almqvist had previously developed a library of compounds that targeted pili, and they screened through this database to find a compound that prevented E. faecalis  from binding (4). The search produced a surprising result. They identified a compound that suppressed E. faecalis, but not by affecting pili. The compound, explained Caparon, was “actually killing the Enterococci.”  The team then modified the structure of the molecule to enhance its antibiotic effect, creating a class of compounds dubbed the GmPcides because they worked exclusively against Gram-positive bacteria. In 2022, the team showed off a GmPcide called PS757 that killed a swathe of bacteria resistant to other first-line antibiotics inside a petri dish arena (5).

But infections like those of S. pyogenes, which cause a range of diseases from strep throat to the flesh-eating necrotizing fasciitis, are much easier to treat in vitro, according to Caparon. 

Necrotizing fasciitis infects connective tissue — fascia — underneath the skin. The disease moves fast; it can destroy an inch of fascia in an hour (6). In severe infections, treatment options include removing large chunks of tissue or even entire limbs. The infection represented a major test for the new drug class. 

PS757 passed with flying colors. 

Mice with S. pyogenes  infections that were locally injected with PS757 had reduced tissue damage and lower bacteria levels. Their wounds healed more quickly — an improvement that was linked to the impairment of proteins that bacteria use to increase their virulence and spread. Caparon said that the GmPcide’s antibacterial mechanism remained unclear. “That's something we're working really, really hard on trying to identify,” he added.

The results are promising, said Chris LaRock, a microbiologist at Emory University who was not involved in the study. Some bacteria spit out toxins as they die, meaning that gold-standard drugs must kill them while also suppressing their protein machinery. The results suggest that GmPcides could meet this mark. “They’re not only killing the bacteria, but they're inhibiting some of its key virulence factors,” said LaRock. 

The team’s next steps are pharmacodynamics and pharmacokinetics studies to calculate an exact dose and treatment schedule, which are key steps towards trialing the compound in humans. What’s clear is that as antibiotic resistance grows, new drugs are urgently needed. Collaborative studies and research are the key, said LaRock. “It's a big science challenge, and it's going to just take a lot of people working together to make it to those next steps,” he said.

References

1. Stennett, H.L., Back, C.R., & Race, P.R. Derivation of a precise and consistent timeline for antibiotic development. Antibiotics (Basel)  11, 1237 (2022).
2. Zampaloni, C. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature  625, 566-571 (2024).
3. Zou, Z. et al. Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection. Sci Adv  10, eadn7979 (2024). 
4. Chorell, E. et al. Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: Pilicides with increased antivirulence activity. J Med Chem  53, 5690–5695 (2010).
5. Nye, T.M. et al. Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics. Proc Natl Acad Sci U S A 119, e2210912119 (2022).
6. Misiakos, E.P. et al. Current concepts in the management of necrotizing fasciitis. Front Surg  1, 36 (2014).