SASP gene delivery: A novel antibacterial approach

Abstract

Antibiotic resistance is a global problem, and with bacteria having developed resistance to all approved antibacterial agents there is a growing need for innovative solutions. Phico Therapeutics has developed a new class of antibacterial agent, a platform technology called SASPject. SASPject comprises modified, disabled bacterial viruses (bacteriophages) injecting a gene encoding an antibacterial protein, SASP, into target bacteria. SASP, or Small, Acid-soluble Spore Protein(s), inactivate bacterial DNA in a non-sequence-specific manner so their activity is unaffected by DNA mutations. Selected pathogens can be targeted, avoiding the normal flora. A Staphylococcus aureus-targeted SASPject, PT1.2, developed for the nasal decolonization of S. aureus, including methicillin-resistant (MRSA) strains, is expected to complete phase I in 2009. SASPject PT1.2 shows good in vitro activity against a wide range of diverse clinical S. aureus isolates, including MRSA strains. A systemic SASPject PT1.2, and SASPjects targeted against Clostridium difficile and multidrug-resistant Gram-negative organisms are in development. The SASPject technology could represent a new paradigm in antibacterial therapeutics.

CRISPR Interference Can Prevent Natural Transformation and Virulence Acquisition during In Vivo Bacterial Infection

“…A high rate of transfer is fundamental for the success of this method. Currently there are technologies that use both conjugative plasmids (Filutowicz et al, 2008) and bacteriophage encapsidation (Fairhead, 2009) to deliver toxin genes to (and thus kill) pathogenic bacteria. We believe that the same technologies can be used to deliver engineered CRISPR/Cas systems that would kill cells containing target sequences such as antibiotic resistance genes or virulence factors, a specificity that cannot be achieved with other antimicrobials.…”

Development of DinQ from Escherichia coli as an anti-cell-envelope antibiotic

“…Therefore, dinQ was integrated into a lacI-inducible M13-based phagemid (pControl without and pDinQ with dinQ) so that recombinant filamentous bacteriophage particles could be produced via the use of R408 helper phage [2]. Previous work has shown that bacteriophages can be efficient delivery vehicles for genetic elements that interfere with the bacterium [3] or that express proteins which disrupt the structure of DNA [4]. E. coli strain ER2738 transformed with the phagemid system and in the exponential phase rapidly stopped dividing upon induction with isopropyl ␤-d-1-thiogalactopyranoside (IPTG).…”

Bacteriophage-based synthetic biology for the study of infectious diseases

“…More recently, M13-derived particles were used to express a lethal mutant of catabolite activator protein in E. coli O157:H7, a foodborne pathogen that causes outbreaks of hemorrhagic colitis [87]. Biotechnology companies have also begun to make use of recombinant phage methods, such as virus-like particles that deliver genes encoding small, acid-soluble proteins to cause toxicity to target cells through non-specific binding to DNA [88]. …”