Biofilm Tolerance Emerges as Key Driver of Antibiotic Treatment Failure (Review, Oct 2026) From biofilm tolerance to antimicrobial resistance: molecular adaptation strategies and emerging therapeutic vulnerabilities in resistant pathogens Other

[Michael Harrop]

https://bioengineer.org/biofilm-tolerance-emerges-as-key-driver-of-antibiotic-treatment-failure/
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2026.1988464/full

A review that lists possible strategies for tackling biofilms.

On the therapeutic front, the review proposes targeting the vulnerabilities that biofilm adaptation itself creates, while noting that nearly all such strategies remain experimental or preclinical. Matrix sensitization with DNase I, dispersin B, proteases or alginate lyases can loosen biofilm structure and improve antimicrobial access, but dispersal alone may release viable cells, supporting a combined disrupt-and-kill approach. Quorum-quenching, c-di-GMP modulation, persister-directed strategies such as metabolic resensitization and toxin-antitoxin targeting, and efflux pump inhibitors each face limitations from pathway redundancy, species specificity and toxicity. Bacteriophage therapy, synthetic antimicrobial peptides of the PS1 series, which inhibited drug-resistant P. aeruginosa and S. aureus biofilms in preclinical models, and nanoparticle delivery systems including chitosan, zinc oxide and silver formulations show promise in animal or laboratory studies but lack human biofilm evidence. CRISPR interference targeting the luxS quorum-sensing gene reduced E. coli biofilm formation in proof-of-concept work.

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Abstract​

Bacterial biofilms are highly structured microbial communities which allow organisms to persist under different environmental challenges such as limitation of nutrients, oxidative stress, host immune defense, and antimicrobial agents. While antimicrobial resistance (AMR) has been well recognized as a key factor contributing to treatment failure, more and more evidence reported that biofilm-associated persistence is initially caused by antimicrobial tolerance rather than genetically encoded resistance.

Tolerance is a change in physiology that enables the bacterial population to persist through a temporary exposure to an antimicrobial agent, while resistance is a stable heritable alteration that confers a decreased susceptibility to an antimicrobial agent. In biofilms, the bacteria are distributed in a heterogeneous manner in different ecological niches with different metabolic activities, oxygen gradients, stress responses and nutrient accessibility. This heterogeneity gives rise to specialized subpopulations, including dormant persisters that serve as reservoirs for further evolutionary adaptation.

Biofilm development results in a selective environment that allows the pressure of antimicrobial agents to induce molecular adaptation through remodelling of extracellular polymeric substance (EPS), metabolic reprogramming, oxidative stress management, quorum sensing, cyclic di-guanosine monophosphate (c-di-GMP) signaling, efflux activation, horizontal gene transfer and diversification via mutations. Such processes form a continuum of tolerance–resistance, with short-term survival processes potentially leading to the development and fixation of resistant phenotypes. Traditional antimicrobial strategies, mainly relying on planktonic susceptibility testing, fail in the resilience of biofilms, necessitating biofilm-specific therapeutic strategies.

Here, we review an integrated framework that describes the way in which bacterial biofilms move from antimicrobial tolerance to resistance evolution. We focus on strategies to intercept biofilm adaptation before stable resistance is achieved, using a combination of evolutionary microbiology, molecular regulation, single-cell biology and therapeutic innovation.

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