Despite the successful use of antibacterials, the emergence of multidrug-resistant bacteria has become a serious threat to global healthcare. In this era of antibacterial crisis, bacteriophages (phages) are being explored as an antibacterial treatment option since they possess a number of advantages over conventional antibacterials, especially in terms of specificity and biosafety; phages specifically lyse target bacteria while not affecting normal and/or beneficial bacteria and display little or no toxicity in that they are mainly composed of proteins and nucleic acids, which consequently significantly reduces the time and cost involved in antibacterial development. However, these benefits also create potential issues regarding antibacterial spectra and host immunity; the antibacterial spectra being very narrow when compared to those of chemicals, with the phage materials making it possible to trigger host immune responses, which ultimately disarm antibacterial efficacy upon successive treatments. In addition, phages play a major role in horizontal gene transfer between bacterial populations, which poses serious concerns for the potential of disastrous consequences regarding antibiotic resistance. Fortunately, however, recent advancements in synthetic biology tools and the speedy development of phage genome resources have allowed for research on methods to circumvent the potentially disadvantageous aspects of phages. These novel developments empower research which goes far beyond traditional phage therapy approaches, opening up a new chapter for phage applications with new antibacterial platforms. Herein, we not only highlight the most recent synthetic phage engineering and phage product engineering studies, but also discuss a new proof-of-concept for phage-inspired antibacterial design based on the studies undertaken by our group.
KatA is the major catalase required for hydrogen peroxide (H2O2) resistance and acute virulence in Pseudomonas aeruginosa PA14, whose transcription is driven from the promoter (katAp1) located at 155 nucleotide (nt) upstream of the start codon. Here, we identified another promoter (katAp2), the +1 of which was mapped at the 51 nt upstream of the start codon, which was responsible for the basal transcription during the planktonic culture and down-regulated upon H2O2 treatment under the control by the master regulator of anaerobiosis, Anr. To dissect the roles of the dual promoters in conditions involving KatA, we created the promoter mutants for each -10 box (p1m, p2m, and p1p2m) and found that katAp1 is required for the function of KatA in the logarithmic growth phase during the planktonic culture as well as in acute virulence, whereas katAp2 is required for the function of KatA in the stationary phase as well as in the prolonged biofilm culture. This dismantling of the dual promoters of katA sheds light on the roles of KatA in stress resistance in both proliferative and growth-restrictive conditions and thus provides an insight into the regulatory impacts of the major catalase on the survival strategies of P. aeruginosa.
YM155 is a clinically evaluated anticancer with a fused naphthoquinone-imidazolium scaffold. In this study, we demonstrated that based on weak or cryptic antibacterial activity of YM155 against methicillin-resistant
Staphylococcus aureus
(MRSA) (MIC of 50 μg/ml), some congeneric compounds with short alkyl chains (e.g., c5 with a hexyl chain) at the N3 position of the scaffold, displayed more potent antibacterial activity against MRSA (MIC of 3.13 μg/ml), which is in a clinically achievable range. Their antibacterial activity was evident against Gram-negative bacteria, only in the presence of the outer membrane-permeabilizing agent, polymyxin B. The antibacterial efficacy of c5 was confirmed using the
Drosophila
systemic infection model. We also characterized five spontaneous c5-resistant MRSA mutants that carry mutations in the
ubiE
gene, for quinone metabolism and respiratory electron transfer, and subsequently exhibited reduced respiration activity. The antibacterial activity of c5 was compromised either by an antioxidant,
N
-acetylcysteine, or in an anaerobic condition. These suggest that the antibacterial mechanism of c5 involves the generation of reactive oxygen species (ROS), presumably during respiratory electron transport. This study provides an insight into “drug redirecting,” through a chemical modification, based on an ROS-generating pharmacophore.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.