Gram-Negative Bacterial Lysins

Abstract

Antibiotics have had a profound impact on human society by enabling the eradication of otherwise deadly infections. Unfortunately, antibiotic use and overuse has led to the rapid spread of acquired antibiotic resistance, creating a major threat to public health. Novel therapeutic agents called bacteriophage endolysins (lysins) provide a solution to the worldwide epidemic of antibiotic resistance. Lysins are a class of enzymes produced by bacteriophages during the lytic cycle, which are capable of cleaving bonds in the bacterial cell wall, resulting in the death of the bacteria within seconds after contact. Through evolutionary selection of the phage progeny to be released and spread, these lysins target different critical components in the cell wall, making resistance to these molecules orders of magnitude less likely than conventional antibiotics. Such properties make lysins uniquely suitable for the treatment of multidrug resistant bacterial pathogens. Lysins, either naturally occurring or engineered, have the potential of being developed into fast-acting, narrow-spectrum, biofilm-disrupting antimicrobials that act synergistically with standard of care antibiotics. This review focuses on newly discovered classes of Gram-negative lysins with emphasis on prototypical enzymes that have been evaluated for efficacy against the major antibiotic resistant organisms causing nosocomial infections.

Lysins breaking down the walls of Gram-negative bacteria, no longer a no-go

“…Several lysins have been reported to have an intrinsic antibacterial activity against a variety of Gram-negative pathogens, a feature which was not anticipated. A. baumannii appears as the most sensitive species for currently unknown reasons [7,8]. Some of these lysins have an unusually broad spectrum covering both Gram-negative and Gram-positive strains [9,10].…”

“…Based on analyses of truncated lysin variants, there is a growing consensus that the mechanism of action of many of these lysins is based on a self-promoted uptake mechanism induced by a Cterminal amphipathic helix that interacts with the OM, followed by active peptidoglycan degradation by the Nterminal enzymatic domain. In some cases, a positively charged hexahis-tag may further enhance the uptake [7,8,11]. In addition, peptides derived from the C-terminal helix of some of these lysins [7,12,13], or engineered variants thereof, [12,13] have demonstrated in vitro and in vivo activity.…”

Phages in Anaerobic Systems

“…Using models such as Escherichia coli , Pseudomonas aeruginosa , Bacillus subtilis or Staphylococcus aureus , it has been possible to show that there are differences in the phage infection mechanisms for Gram-positive and Gram-negative bacteria, mainly due to the composition of their walls [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. The type of receptor and the way in which the genetic material is injected are aspects that change according to the composition of the cell wall and these have been very well described.…”

Nontraditional Antibiotics—Challenges and Triumphs

“…The concept paper by Azeredo da Silveira and Shorr provides an excellent case study on CAL02, a liposome-derived anti-virulence trap designed to sequester bacterial toxins by acting as a decoy mimic of cellular lipid platforms [4]. The three review articles by Zurawski and McLendon [5], Nikolich and Filippov [6], and Ghose and Euler [7] give a superb timely survey of how monoclonal antibodies, bacteriophages and lysins, respectively, are currently being explored in the treatment of bacterial infections. The utility and future potential of antibodies to treat bacterial infections is only just being realized now, despite a successful history in other therapeutic areas.…”

“…Bacteriophage endolysins are another product that have been studied intensively, albeit generally against Gram-positive organisms due to the Gram-negative impermeability barrier. Speaking from a commercial drug developer's viewpoint, Ghose and Euler give a unique detailed account of newly discovered lysins with Gram-negative activity currently in the early stages of development [7]. This will no doubt be of great interest to developers working in the field.…”