CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens

Area of Science:

• Immunology
• Microbiology
• Drug Discovery

Background:

• Antimicrobial resistance (AMR) is a growing global health threat, necessitating novel therapeutic strategies.
• The emergence of multidrug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant and colistin-resistant strains, poses a significant clinical challenge.
• Existing antibiotics are losing efficacy, highlighting the urgent need for innovative treatments against resistant pathogens.

Purpose of the Study:

• To investigate the antimicrobial capacity of human CXC chemokines CXCL9 and CXCL10 against MDR Gram-negative pathogens.
• To elucidate the mechanisms underlying chemokine-mediated killing of resistant bacteria, including those with specific resistance determinants.
• To explore the potential of chemokines as a novel therapeutic approach for treating infections caused by antibiotic-resistant 'superbugs'.

Main Methods:

• Testing the bactericidal activity of CXCL9 and CXCL10 against MDR Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1 (NDM-1)-producing *Klebsiella pneumoniae* and colistin-resistant *Enterobacteriaceae* harboring MCR-1.
• Analyzing the susceptibility of colistin-resistant *K. pneumoniae* isolates with mutations in the PmrA/PmrB two-component system or MgrB gene to chemokine-mediated killing.
• Investigating the impact of lipopolysaccharide modification (phosphoethanolamine and 4-amino-4-deoxy-l-arabinose) on bacterial susceptibility to CXCL9 and CXCL10.

Main Results:

• CXCL9 and CXCL10 effectively killed MDR Gram-negative bacteria, including NDM-1-producing *K. pneumoniae* and MCR-1-positive colistin-resistant *Enterobacteriaceae*.
• Colistin-resistant *K. pneumoniae* with PmrA/PmrB mutations were susceptible to chemokine-mediated killing.
• Loss of MgrB-mediated negative regulation of PhoP/PhoQ signaling variably impacted bacterial susceptibility to CXCL9 and CXCL10, indicating strain-specific resistance mechanisms.

Conclusions:

• Human chemokines CXCL9 and CXCL10 possess significant bactericidal activity against critical MDR Gram-negative pathogens.
• These findings provide mechanistic insights into chemokine-mediated antimicrobial effects and highlight the complexity of colistin resistance determinants.
• CXCL9 and CXCL10 represent a promising therapeutic avenue for developing novel treatments against challenging antibiotic-resistant infections.