Abstract
Nosocomial and community-acquired infections caused by multidrug resistant bacteria represent a major human health problem. Thus, there is an urgent need for the development of antibiotics with new modes of action. In this study, we investigated the antibacterial characteristics and mode of action of a new antimicrobial compound, SPI031 (N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol), which was previously identified in our group. This compound exhibits broad-spectrum antibacterial activity, including activity against the human pathogens Staphylococcus aureus and Pseudomonas aeruginosa. We found that SPI031 has rapid bactericidal activity (7-log reduction within 30 min at 4x MIC) and that the frequency of resistance development against SPI031 is low. To elucidate the mode of action of SPI031, we performed a macromolecular synthesis assay, which showed that SPI031 causes non-specific inhibition of macromolecular biosynthesis pathways. Liposome leakage and membrane permeability studies revealed that SPI031 rapidly exerts membrane damage, which is likely the primary cause of its antibacterial activity. These findings were supported by a mutational analysis of SPI031-resistant mutants, a transcriptome analysis and the identification of transposon mutants with altered sensitivity to the compound. In conclusion, our results show that SPI031 exerts its antimicrobial activity by causing membrane damage, making it an interesting starting point for the development of new antibacterial therapies.
Highlights
Bacterial infections are among the most serious threats to human health
At 1x Minimum Inhibitory Concentration (MIC) of SPI031, the bactericidal endpoint was achieved after 24 h, with a reduction of colony forming units (CFU) by almost 6 log units
We demonstrated that SPI031-functionalised titanium surfaces show significant antibacterial activity both in vitro and in vivo [17]
Summary
Bacterial infections are among the most serious threats to human health. Millions of people acquire such infections each year, leading to increased mortality rates worldwide and an economic burden on society [1]. The Gram-positive pathogen Staphylococcus aureus is one of the major causes of nosocomial and community-acquired infections [2]. This bacterium accounts for 12.3% of all nosocomial infections in Europe, resulting in bacteremia and surgical wound infections, and is the main cause of implant-related infections [3,4]. The emergence of methicillin-resistant S. aureus has severely complicated the treatment of such infections. Glycopeptide antibiotics such as vancomycin are often used to treat both methicillin-susceptible and methicillin-resistant infections [6,7]. In the past few years, there have been several reports of vancomycin-resistant S. aureus infections [8,9,10]
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