Rapid kill assessment of an N-arylated NH125 analogue against drug-resistant microorganisms

Abstract

While a number of disinfection techniques are employed in healthcare units, the eradication of drug-resistant microorganisms remains a challenge. We recently reported N-arylated NH125 analogue 1, which demonstrated potent biofilm eradication and antibacterial activities against a panel of drug-resistant pathogens. The broad-spectrum activities observed for 1 along with its rapid eradication of MRSA persister cells suggested that this agent, and related analogues, can serve as disinfectants for antibiotic resistant pathogens in healthcare settings. Here, we report the rapid bactericidal activities of 1 against a panel of exponentially-growing, drug-resistant pathogens. Against MRSA, MRSE, VRE and MDR A. baumannii, 1 eradicated bacterial cells after five minutes when tested at 50 μM (3- to 6-log reduction of CFU per mL). We highlighted the rapid killing activities by demonstrating that 1 eradicates 99.99% of viable MRSA 1707 cells in one minute (50 μM, 4-log reduction of CFU per mL). In addition, 1 rapidly eradicated fungal pathogen C. neoformans in kill kinetic experiments. A solution of 1 demonstrated similar shelf stability to known disinfectant BAC-16 when tested up to 111 days after being stored. Collectively, our data highlights the potential of 1 to be used as a disinfecting agent to prevent healthcare-associated, drug-resistant infections.

Fig. 1. Reported chemical synthesis and antibacterial activities of N-arylated NH125 analogue 1.

Fig. 2. Kill kinetic profiles of 1 against exponentially-growing bacteria, including: A) MRSA 1707, B) MRSE 35984, C) VRE 700221 and D) MDR A. baumannii 1794.

Fig. 3. A) Kill kinetics of exponentially-growing C. neoformans 66031. B) Kill kinetics of exponentially-growing MRSA 1707 treated with variable concentrations of 1 and BAC-16. C) Efficacy of 18 day old solutions of 1 and BAC-16 (50 μM; CFU mL^–1 in MRSA cultures after 10 minutes of exposure to compounds). D) Efficacy of new versus 111 day old solutions of 1 and BAC-16 (50 μM; CFU mL^–1 in MRSA cultures after 10 minutes of exposure to compounds). *P-value <0.01, **P-value <0.0005. NS: not significant.