Targeted Depletion of Bacteria from Mixed Populations by Programmable Adhesion with Antagonistic Competitor Cells

Abstract

Selective and targeted removal of individual species or strains of bacteria from complex communities can be desirable over traditional, broadly acting antibacterials in several contexts. However, generalizable strategies that accomplish this with high specificity have been slow to emerge. Here we develop programmed inhibitor cells (PICs) that direct the potent antibacterial activity of the type VI secretion system (T6SS) against specified target cells. The PICs express surface-displayed nanobodies that mediate antigen-specific cell-cell adhesion to effectively overcome the barrier to T6SS activity in fluid conditions. We demonstrate the capacity of PICs to efficiently deplete low-abundance target bacteria without significant collateral damage to complex microbial communities. The only known requirements for PIC targeting are a Gram-negative cell envelope and a unique cell surface antigen; therefore, this approach should be generalizable to a wide array of bacteria and find application in medical, research, and environmental settings. ll

Co-infection of Malassezia sympodialis With Bacterial Pathobionts Pseudomonas aeruginosa or Staphylococcus aureus Leads to Distinct Sinonasal Inflammatory Responses in a Murine Acute Sinusitis Model

“…P. aeruginosa possesses 3 genes for T6SS, H1-, H2-, and H3-T6SS, and H2- and H3-T6SS act not only against prokaryotes but also against eukaryotes (Hood et al, 2010 ; Trunk et al, 2018 ). A recently published study showed that programmed inhibitor cells can target bacterial species in a complex microbial community using T6SS (Ting et al, 2020 ), indicating a potential role for T6SS in altering microbiota composition.…”

In the Age of Synthetic Biology, Will Antimicrobial Peptides be the Next Generation of Antibiotics?

“…An alternative approach to be considered is engineering microbes for therapy in the form of synthetic probiotics, which can lead to the controlled release of these microbial strains providing localised therapeutics under specific conditions. There are many examples in the literature of probiotic strains that have been engineered to act as drug delivery vectors at the site of infection [ 72 , 83 ]. However, there are still multiple challenges in the clinical application of engineered probiotics, such as stable long-term colonization of the niche [ 84 ].…”

Potential of Skin Microbiome, Pro- and/or Pre-Biotics to Affect Local Cutaneous Responses to UV Exposure

“…Finally, recent reports have shown that antibiotic treatment or selective enrichment of certain microbial species in the gut can indeed limit the effectiveness of immune check point therapy in cutaneous melanoma [ 97 , 98 ]. Interestingly, a recent study demonstrated targeted depletion of bacteria from a mixed population by programmed inhibitor cells that can direct the antibacterial activity against specified target cells using the type VI secretion system (T6SS) [ 99 ]. Such an approach where topical treatment selectively enriches skin commensals or targets specified microbes (pathogenic), known to be involved in immune responses [ 100 ], could also be envisioned for modulating UVR-induced immune suppression and the efficacy of phototherapy ( Figure 1 ).…”