NJ026-0402

Endolysins from Cutibacterium acnes phages as alternative antimicrobials

Muhammad Adeel Hasnain1 and Gi-Seong Moon1,2*

1Major in IT·Biohealth Convergence, Department of IT·Energy Convergence, Graduate School, Korea National University of Transportation, Chungju 27469, Korea. 2Department of Biotechnology, Korea National University of Transportation, Jeungpyeong 27909, Korea

Correspondence to: Gi-Seong Moon, gsmoon@ut.ac.kr

Received: April 3, 2026; Revised: May 26, 2026; Accepted: June 11, 2026; Published: June 12, 2026

NATPRO J. 2026, 3, 23-26 

https://doi.org/10.23177/NJ026.0402 

Copyright ©  The Asian Society of Natural Products

Abstract

The rising antibiotic resistance of Cutibacterium acnes and the disruption of the skin microbiome have necessitated the development of alternative acne therapies. Bacteriophage-derived endolysins have emerged as a promising, microbiome-friendly antimicrobial strategy. These enzymes rapidly and specifically degrade the bacterial cell wall, selectively targeting pathogens without harming beneficial microbiota. Furthermore, endolysins exhibit a low propensity for resistance development and are highly effective against biofilms. Recent advancements in protein engineering—focusing on the enzymatic active domain (EAD) and cell wall-binding domain (CBD)—have enabled the structural optimization of recombinant endolysins for enhanced therapeutic efficacy. This paper outlines the mechanism of action, technological developments, and patent trends of C. acnes-targeting endolysins, highlighting their significant clinical and commercial potential as next-generation targeted topical therapeutics in dermatological care.

Keywords

bacteriophage, endolysin, Cutibacterium acnes

1. Background

Acne vulgaris is one of the most prevalent dermatological disorders worldwide, affecting a substantial proportion of adolescents and adults. The pathogenesis of acne is multifactorial, involving sebum overproduction, follicular hyperkeratinization, inflammation, and microbial dysbiosis. Among the microbial contributors, Cutibacterium acnes plays a central role by colonizing pilosebaceous units and inducing inflammatory responses through host immune activation. Conventional acne treatments rely heavily on topical and systemic antibiotics, including clindamycin and tetracyclines. However, the long-term use of antibiotics has led to the emergence of resistant strains of C. acnes and disruption of the skin microbiome. These limitations have prompted the exploration of alternative antimicrobial strategies that are both effective and microbiome-friendly [1].

Among the most promising alternatives are bacteriophage-derived endolysins, enzymes that degrade bacterial cell walls and induce rapid cell lysis. Endolysins are naturally produced during the late stage of the bacteriophage lytic cycle, where they hydrolyze peptidoglycan (PG) to release progeny phages [2]. Structurally, most endolysins targeting Gram-positive bacteria exhibit a modular organization consisting of an enzymatically active domain (EAD) responsible for cleaving specific bonds within the PG, and a cell wall binding domain (CBD) that confers high specificity toward target bacteria [3] . This modularity enables precise targeting and has facilitated extensive protein engineering approaches to enhance their antimicrobial properties.

Several unique characteristics distinguish endolysins from conventional antibiotics and make them attractive candidates for next-generation antibiotics. First, endolysins exhibit rapid bactericidal activity by directly degrading the structural integrity of the bacterial cell wall, leading to immediate osmotic lysis [4]. Second, their high specificity allows selective targeting of pathogenic bacteria without disrupting beneficial microbiota, thereby reducing dysbiosis and associated complications [5]. Third, the likelihood of resistance development against endolysins is considered low, as they target highly conserved and essential components of the bacterial cell wall, and their extracellular mode of action bypasses common resistance mechanisms such as efflux pumps and intracellular drug modification. Additionally, many endolysins possess multiple catalytic domains that cleave different bonds within the PG, further reducing the probability of resistance emergence [6].

Another significant advantage of endolysins is their effectiveness against biofilms, which are notoriously resistant to conventional antibiotics. Endolysins can penetrate biofilm matrices and directly lyse embedded bacterial cells, including persister populations, thereby offering a powerful strategy for treating chronic and device-associated infections [7]. Furthermore, endolysins demonstrate strong synergistic effects when combined with antibiotics or antimicrobial peptides, enhancing bacterial clearance and potentially restoring antibiotic efficacy against resistant strains [8]. Advances in protein engineering have also enabled the development of modified endolysins, such as artilysins and peptide-fused constructs, which can overcome the outer membrane barrier of Gram-negative bacteria and expand their antibacterial spectrum.

2. Technology: Mechanism and Engineering of Endolysins

Endolysins are peptidoglycan hydrolases produced by bacteriophages during the final stage of their lytic cycle to degrade the host bacterial cell wall, facilitating phage progeny release. Structurally, endolysins typically consist of two functional domains: an enzymatically active domain (EAD) responsible for catalytic cleavage of peptidoglycan bonds, and a cell wall-binding domain (CBD) that confers target specificity [3].

The antibacterial activity of endolysins is mediated through rapid hydrolysis of the bacterial cell wall, leading to osmotic lysis and cell death. This mechanism is particularly effective against Gram-positive bacteria, where the peptidoglycan layer is directly accessible. Importantly, endolysins act externally when applied as recombinant proteins, eliminating the need for phage delivery.

Recent technological advancements have focused on engineering endolysins to enhance their therapeutic potential. These approaches include domain truncation, domain swapping, and fusion protein design. Domain-specific studies have revealed that individual domains can exhibit distinct antibacterial properties, enabling the development of optimized constructs with improved activity or stability [9]. Additionally, strategies to enhance solubility and expression, such as fusion tags or sequence modifications, have facilitated large-scale recombinant production.

In our recent work, we investigated the antibacterial activity of domain-specific constructs of a recombinant endolysin targeting C. acnes. Comparative analysis of N-terminal and C-terminal domains demonstrated differential lytic activity, highlighting the importance of structural organization in determining antibacterial efficacy. Specifically, the purified N-terminal domain (50 µg/mL) exhibited approximately 1.5-fold greater activity as compared to full-length endolysin of same concentration. Similarly, N-terminal domain was about 2 times more effective in lytic activity than C-terminal domain which showed negligible antibacterial activity [9]. These findings support the feasibility of rational endolysin design for targeted therapeutic applications.

This letter specifically focuses on the emerging application of C. acnes phage-derived endolysins in acne management. In addition to discussing recent advances in endolysin engineering, we highlight domain-specific antibacterial activity using recent experimental evidence from recombinant anti-C. acnes endolysin constructs, emphasizing their translational relevance for dermatological applications. Furthermore, this letter integrates current perspectives on product development, patent activity, and market trends, providing a focused overview of the clinical and commercial potential of engineered endolysins for acne therapy.

3. Product Potential and Applications

Although endolysin-based therapeutics are still in the developmental stage, their potential applications in dermatology are significant. Recombinant endolysins targeting C. acnes can be formulated as topical treatments, including creams, gels, or serums, offering a targeted approach to acne management without disrupting commensal skin microbiota [2].

Such products could be positioned as next-generation cosmeceuticals or prescription therapeutics, particularly for patients with antibiotic-resistant acne. Additionally, endolysins may be combined with existing treatments to enhance efficacy while reducing antibiotic dosage [10].

However, several challenges must be addressed for successful product development. These include protein stability under formulation conditions, efficient delivery into the pilosebaceous unit, and maintenance of enzymatic activity on the skin surface [7]. Advances in formulation science, such as encapsulation and nanocarrier systems, may help overcome these limitations [11].

4. Patent Trends

Recent patent developments strongly support the therapeutic potential of endolysins, particularly against Gram-positive pathogens. For instance, the European patent [12] describes a recombinant lysin with potent and selective activity against Streptococcus agalactiae, including multidrug-resistant strains, and demonstrates stability across physiologically relevant pH ranges, highlighting its suitability for clinical applications. In addition, the granted patent [13]  demonstrates the incorporation of lysins such as lysostaphin into formulations targeting Gram-positive bacteria like Staphylococcus aureus, further supporting their translational potential in dermatological applications. Collectively, these patents emphasize the specificity, modularity, and clinical adaptability of endolysins against Gram-positive pathogens. Given that C. acnes is also a Gram-positive bacterium with a well-defined peptidoglycan structure, similar strategies involving recombinant or engineered endolysins could be effectively extended to acne-associated infections, highlighting a promising avenue for targeted, resistance-mitigating antimicrobial therapy.

5. Market Trends

The rapid emergence of antimicrobial resistance (AMR) has become a major global health concern, with bacterial AMR associated with approximately 4.95 million deaths worldwide in 2019, including 1.27 million deaths directly attributable to resistant infections [14]. The growing prevalence of antibiotic-resistant pathogens, coupled with the limited efficacy and adverse effects of conventional antibiotics, has intensified the search for alternative antimicrobial strategies. In parallel, the global acne treatment market continues to expand due to the high worldwide burden of acne, which affects nearly 9.4% of the population, along with increasing consumer awareness and advances in dermatological therapies. Recent market analyses project that the global acne treatment market will increase from approximately USD 12.19 billion in 2025 to USD 19.55 billion by 2034, with a compound annual growth rate (CAGR) of 5.40% [15].

Although antibiotics remain among the most widely used therapeutic options for acne management, increasing concerns regarding antimicrobial resistance are driving interest toward targeted and microbiome-friendly alternatives. In this context, bacteriophage-derived endolysins have emerged as promising antimicrobial agents because of their potent bacteriolytic activity against antibiotic-resistant bacteria through mechanisms distinct from those of conventional antibiotics [16]. Supporting this growing interest, the global endolysin bactericide market was valued at approximately USD 445 million in 2024 and is projected to reach nearly USD 1.78 billion by 2033, with an estimated CAGR of 16.7%, reflecting increasing clinical and commercial interest in endolysin-based therapeutics [17].

References

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9. Lee, J-H.; Hasnain, M.A.; Park J-H; Choi, W-H.; Moon, G-S. Comparative Antibacterial Activity of N-Terminal and C-Terminal Domains of a Recombinant Endolysin against Cutibacterium acnes. Appl Environ Microbiol. 2025. 91, e01168-25. https://doi.org/10.1128/aem.01168-25 

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16. Vander Elst, N. Clinical Implementation of Endolysins Targeting Gram-Positive Bacteria Points toward a Combination Strategy with Standard-of-Care Antibiotics: A Selective Review. Eur J Med Res. 2026, 31, 152. https://doi.org/10.1186/s40001-025-03655-4 

17. https://researchintelo.com/report/endolysin-bactericide-market

Cite this article;

Hasnain, M. A.; Gi-Seong Moon, G.-S. Endolysins from Cutibacterium acnes phages as alternative antimicrobials. NATPRO J. 2026, 3, 23-26