TY - JOUR
T1 - Enhanced therapeutic window for antimicrobial Pept-ins by investigating their structure-activity relationship
AU - Wu, Guiqin
AU - Khodaparast, Laleh
AU - Khodaparast, Ladan
AU - De Vleeschouwer, Matthias
AU - Louros, Nikolaos
AU - Gallardo, Rodrigo
AU - Yi, Pengpeng
AU - Rousseau, Frederic
AU - Schymkowitz, Joost
N1 - Publisher Copyright:
© 2023 Wu et al.
PY - 2023/3
Y1 - 2023/3
N2 - The overconsumption and inappropriate use of antibiotics is escalating antibiotic resistance development, which is now one of the 10 top threats to global health. Introducing antibiotics with a novel mode of action into clinical use is urgently needed to address this issue. Deliberately inducing aggregation of target proteins and disrupting protein homeostasis in bacteria via amyloidogenic peptides, also called Pept-ins (from peptide interferors), can be lethal to bacteria and shows considerable promise as a novel antibiotic strategy. However, the translation of Pept-ins into the clinic requires further investigation into their mechanism of action and improvement of their therapeutic window. Therefore, we performed systematic structure modifications of 2 previously discovered Pept-ins, resulting in 179 derivatives, and investigated the corresponding impact on antimicrobial potency, cellular accumulation, and ability to induce protein aggregation in bacteria, in vitro aggregation property, and toxicity on mammalian cells. Our results show that both Pept-in accumulation and aggregation of target proteins in bacteria are requisite for Pept-in mediated antimicrobial activity. Improvement of these two parameters can be achieved via increasing the number of arginine residues, increasing Pept-in aggregation propensity, optimizing the aggregate core structure, adopting β-turn linkers, or forming a disulphide bond. Correspondingly, improvement of these two parameters can enhance Pept-in antimicrobial efficacy against wildtype E. coli BL21 used in the laboratory as well as clinically isolated multidrug-resistant strain E. coli ATCC, A. baumannii, and K. pneumoniae.
AB - The overconsumption and inappropriate use of antibiotics is escalating antibiotic resistance development, which is now one of the 10 top threats to global health. Introducing antibiotics with a novel mode of action into clinical use is urgently needed to address this issue. Deliberately inducing aggregation of target proteins and disrupting protein homeostasis in bacteria via amyloidogenic peptides, also called Pept-ins (from peptide interferors), can be lethal to bacteria and shows considerable promise as a novel antibiotic strategy. However, the translation of Pept-ins into the clinic requires further investigation into their mechanism of action and improvement of their therapeutic window. Therefore, we performed systematic structure modifications of 2 previously discovered Pept-ins, resulting in 179 derivatives, and investigated the corresponding impact on antimicrobial potency, cellular accumulation, and ability to induce protein aggregation in bacteria, in vitro aggregation property, and toxicity on mammalian cells. Our results show that both Pept-in accumulation and aggregation of target proteins in bacteria are requisite for Pept-in mediated antimicrobial activity. Improvement of these two parameters can be achieved via increasing the number of arginine residues, increasing Pept-in aggregation propensity, optimizing the aggregate core structure, adopting β-turn linkers, or forming a disulphide bond. Correspondingly, improvement of these two parameters can enhance Pept-in antimicrobial efficacy against wildtype E. coli BL21 used in the laboratory as well as clinically isolated multidrug-resistant strain E. coli ATCC, A. baumannii, and K. pneumoniae.
UR - http://www.scopus.com/inward/record.url?scp=85151339739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85151339739&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0283674
DO - 10.1371/journal.pone.0283674
M3 - Article
C2 - 37000776
AN - SCOPUS:85151339739
SN - 1932-6203
VL - 18
JO - PloS one
JF - PloS one
IS - 3 MARCH
M1 - e0283674
ER -