P-1219. Broad spectrum of activity of AJ-099 against key refractory pathogens in cystic fibrosis lung infections: Pseudomonas aeruginosa and Mycobacterium abscessus

TL;DR

AJ-099 shows strong antibacterial effects against hard-to-treat lung pathogens in cystic fibrosis patients.

Contribution

AJ-099 demonstrates potent in vivo efficacy and low MIC values against Pseudomonas aeruginosa and Mycobacterium abscessus, including drug-resistant strains.

Findings

AJ-099 reduced bacterial burden in MDR P. aeruginosa-infected mice by 3.2 log₁₀ CFU.

AJ-099 had MIC50/90 values of 2/4 μg/mL against M. abscessus clinical isolates.

The compound was effective in both immunocompromised and non-immunocompromised mouse models.

Abstract

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Defects in the CFTR protein impair proper hydration of the cellular surface, leading to dysfunctional mucociliary clearance. These changes increase the risk of infections or co-infections by various bacterial pathogens, including Pseudomonas aeruginosa, non-tuberculous Mycobacteria (NTM) species. The rising prevalence of co-infections involving P. aeruginosa, M. abscessus in CF patients underscores the urgent need for novel therapeutic strategies.In vivo efficacy of AJ-099 against standard PAO1 P. aeruginosaIn vivo efficacy of AJ-099 against MDR P. aeruginosa

In vivo efficacy of AJ-099 against standard PAO1 P. aeruginosa

In vivo efficacy of AJ-099 against MDR P. aeruginosa

Susceptibility testing of AJ-099 was conducted using the broth microdilution method against 78 M. abscessus clinical isolates from Samsung Medical Center in Seoul, Republic of Korea to determine its MIC50 and MIC90 values. Clarithromycin and amikacin resistant M. abscessus strains were included in the study.

The in vivo efficacy of AJ-099 free form and its HCl salt was evaluated in an ICR mouse model, in which mice were immunocompromised with cyclophosphamide and challenged with the standard P. aeruginosa PAO1 strain at an inoculation size of 5 x 106 to 2 x 107 CFU per mouse. The compounds were administrated via intranasal instillation at doses of 8 mg/kg or 16 mg/kg.

Additional in vivo studies were conducted using a non-immunocompromised ICR mouse model infected with a multidrug-resistant (MDR) clinical strain obtained from Samsung Medical Center in Changwon. Mice were challenged with P. aeruginosa (2.5×108 to 1×109 CFU per mouse), and the statistical significance of post-challenge changes in bacterial burden was assessed using one-way ANOVA.Antibacterial activity of AJ-099 against clinical isolates of M. abscessus

Antibacterial activity of AJ-099 against clinical isolates of M. abscessus

AJ-099 exhibits a potent antibacterial activity against various clinical M. abscessus strains, including those resistant to clarithromycin and amikacin. Its MIC50/90 values are 2 and 4 μg/mL, respectively.

In addition, treatment with AJ-099 in murine lung-infection models produced a statistically significant median reduction of 3.2 log₁₀ CFU in the pulmonary burden of multidrug-resistant P. aeruginosa (P < 0.005).

Collectively, these findings support inhaled AJ-099 as a promising therapeutic candidate for treating refractory lung infections in CF patients.

Sanghun Oh, n/a, A&J Science Co., Ltd.: Employee of A&J Science Sungji Jung, n/a, A&J Science Co., Ltd.: Employee of A&J Science Jiyoung Kim, n/a, A&J Science Co., Ltd.: Employee of A&J Science Go-oun Kim, n/a, A&J Science Co., Ltd.: Employee of A&J Science Hee-Jong Hwang, PhD, A&J Science Co., Ltd.: Board Member|A&J Science Co., Ltd.: Ownership Interest

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