Chan-Park, M. | Search bioRxiv

bioRxiv2022

Polyimidazolium protects against an invasive clinical isolate of Salmonella Typhimurium

Frequent outbreaks of Salmonella Typhimurium infection in both the animal and human population with potential for zoonotic transmission pose a significant threat to the public health sector. The rapid emergence and spread of more invasive multidrug-resistant clinical isolates of Salmonella further highlight the need for the development of new drugs with effective broad-spectrum bactericidal activities. Synthesis and evaluation of main-chain cationic polyimidazolium 1 (PIM1) against several gram-positive and gram-negative bacteria have previously demonstrated the efficacy profile of PIM1. The present study focuses on antibacterial and anti-biofilm activities of PIM1 against Salmonella both in vitro and in ovo setting. In vitro, PIM1 exhibited bactericidal activity against all tested three strains of Salmonella at a low dosage of 8 g/ml. Anti-biofilm activity of PIM1 was evident with complete inhibition for the initial attachment of biofilms at 16 g/ml and degradation of pre-formed biofilms in a dose-dependent manner. During the host cell infection process, PIM1 reduces extracellular bacterial adhesion and invasion rates to limit the establishment of infection. Once intracellular, the drug-resistant strain was tolerant and protected from PIM1 treatment. In a chicken egg infection model, PIM1 exhibited therapeutic activity for both Salmonella strains with stationary-phase and exponential-phase inocula. Moreover, PIM1 showed a remarkable efficacy against the stationary phase inocula of drug-resistant Salmonella by eliminating the bacteria burden in >50% of infected chicken egg embryos. Collectively, PIM1 has demonstrated its potential as a drug candidate for treatment of Salmonella infections, as well as a solution to tackle egg contamination issues on poultry farms.

microbiology↗

bioRxiv2019

Combined efficacy of a novel antimicrobial cationic peptide polymer with conventional antibiotics to combat multi-drug resistant pathogens

Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year by 2050 and to cost the global economy 100 trillion USD. Novel approaches and alternatives to conventional antibiotics are urgently required to combat antimicrobial resistance. We have synthesized a chitosan-based oligolysine antimicrobial peptide, CSM5-K5, which targets multidrug resistant (MDR) bacterial species. Here we show that CSM5-K5 exhibits rapid bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin resistant Enterococcus faecalis (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to which each organism is otherwise resistant restores sensitivity to the conventional antibiotic. CSM5-K5 alone significantly reduced pre-formed bacterial biofilm by two-four orders of magnitude and, in combination with traditional antibiotics, reduced pre-formed biofilm by more than two-three orders of magnitude at sub inhibitory concentrations. Moreover, using a mouse excisional wound infection model, CSM5-K5 treatment reduced bacterial burdens by one to three orders of magnitude, and acted synergistically with vancomycin and tetracycline to clear VRE and MDR E. coli, respectively. Importantly, little to no resistance against CSM5-K5 arose for any of the three MDR bacteria during 15 days of serial passage. This work demonstrates the feasibility and benefits of using this synthetic cationic peptide as alternative to, or in combination with, traditional antibiotics to treat infections caused by MDR bacteria.

microbiology↗