The accelerating spread of drug-res

The accelerating spread of drug-resistant bacteria is creating demand for novel
antibiotics. Bactericidal enzymes, such as human lysozyme (hLYZ), are interesting drug candidates
due to their inherent catalytic nature and lack of susceptibility to the resistance mechanisms typically
directed toward chemotherapeutics. However, natural antibacterial enzymes have their own
limitations. For example, hLYZ is susceptible to pathogen derived inhibitory proteins, such as
Escherichia coli Ivy. Here, we describe proof of concept studies demonstrating that hLYZ can be
effectively redesigned to evade this potent lysozyme inhibitor. Large combinatorial libraries of hLYZ
were analyzed using an innovative screening platform based on microbial coculture in hydrogel
microdroplets. Isolated hLYZ variants were orders of magnitude less susceptible to E. coli Ivy yet
retained high catalytic proficiency and inherent antibacterial activity. Interestingly, the engineered
escape variants showed a disadvantageous increase in susceptibility to the related Ivy ortholog from
Pseudomonas aeruginosa as well as an unrelated E. coli inhibitory protein, MliC. Thus, while we have
achieved our original objective with respect to escaping E. coli Ivy, engineering hLYZ for broadspectrum
evasion of proteinaceous inhibitors will require consideration of the complex and varied
determinants that underlie molecular recognition by these emerging virulence factors

ผลลัพธ์ (อังกฤษ) 2:

Drug-resistant bacteria of accelerating the spread is creating demand for novel
antibiotics. Bactericidal enzymes, such As Human lysozyme (HLYZ), are Interesting Drug Candidates
Due to their inherent catalytic Nature and Lack of susceptibility to the resistance Mechanisms typically
directed toward chemotherapeutics. However, Natural Antibacterial enzymes have their own
limitations. For example, HLYZ is susceptible to pathogen derived inhibitory proteins, such As
Escherichia coli Ivy. Here, we describe Proof of Concept Studies demonstrating that HLYZ Can be
redesigned to effectively evade this potent inhibitor lysozyme. Large combinatorial libraries of HLYZ
were analyzed using an innovative Screening Platform based on microbial coculture in hydrogel
Microdroplets. Isolated HLYZ variants were susceptible to E. coli orders of Magnitude Less Ivy yet
retained catalytic High Proficiency and inherent Antibacterial Activity. Interestingly, the Engineered
Escape variants Showed a Disadvantageous increase in susceptibility to the Ivy Related ortholog from
Pseudomonas aeruginosa As well As an unrelated E. coli inhibitory protein, MliC. Thus, while we have
achieved with our Original Objective Respect to escaping E. coli Ivy, Engineering HLYZ for Broadspectrum
Evasion of proteinaceous inhibitors Will Require consideration of the Complex and varied
molecular determinants that underlie Recognition by these emerging virulence factors.