Inhibitors of the Elastase LasB for the Treatment of Pseudomonas aeruginosa Lung Infections

Abstract

Infections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on a nontraditional approach to combat P. aeruginosa-derived infections by targeting its main virulence factor, the elastase LasB. We discovered a new chemical class of phosphonates with an outstanding in vitro ADMET and PK profile, auspicious activity both in vitro and in vivo. We established the mode of action through a cocrystal structure of our lead compound with LasB and in several in vitro and ex vivo models. The proof of concept of a combination of our pathoblocker with levofloxacin in a murine neutropenic lung infection model and the reduction of LasB protein levels in blood as a proof of target engagement demonstrate the great potential for use as an adjunctive treatment of lung infections in humans.

A Review of Antibacterial Candidates with New Modes of Action

“…Release at the site of infection results in proteolysis of host tissue and immune components. Both Antabio and the Helmholtz Institute have received CARB-X funding to advance LasB inhibitors, potentially based on published indane carboxylates such as 107 , , and phosphonates such as 108 , respectively.…”

Disarming Gram-Negative Bacteria in the Fight Against Antimicrobial Resistance

“…I n this issue of ACS Central Science, Hirsch and co-workers report an innovative strategy to treat infections caused by the Gram-negative bacterium Pseudomonas aeruginosa by targeting its main virulence factor, LasB. 1 P. aeruginosa is a multidrug resistant opportunistic bacterium that is listed among the World Health Organization's critical group of pathogens for which new antibiotics are urgently required. 2 Antimicrobial resistance (AMR) is a significant and increasing threat to global public health that was associated with 4.95 million deaths in 2019.…”

“…In this issue of ACS Central Science , Hirsch and co-workers report an innovative strategy to treat infections caused by the Gram-negative bacterium Pseudomonas aeruginosa by targeting its main virulence factor, LasB .…”

“…The p K a values were calculated using Chemicalize. The logD 7.4 values are taken from Konstantinović et al…”