A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

Abstract

Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box genes, not present in the human host. Present in Gram-positive bacteria, T-box genes attenuate transcription with a riboswitch-like element that regulates the expression of aminoacyl-tRNA synthetases and amino acid metabolism genes required for cell viability. PKZ18, the parent of a family of compounds selected in silico from 305,000 molecules, inhibits the function of the conserved T-box regulatory element and thus blocks growth of antibiotic-resistant S. aureus in biofilms. The PKZ18 analog PKZ18-22 was 10-fold more potent than vancomycin in inhibiting growth of S. aureus in biofilms. In addition, PKZ18-22 has a synergistic effect with existing antibiotics, e.g., gentamicin and rifampin. PKZ18-22 inhibits the T-box regulatory mechanism, halts the transcription of vital genes, and results in cell death. These effects are independent of the growth state, planktonic or biofilm, of the bacteria, and could inhibit emergent strains.

A Riboswitch-Driven Era of New Antibacterials

“…More specifically, analog PKZ18-22 exhibited a significant effect on the expression of eight out of 12 T-box regulated genes on MRSA and did not affect the 5′ UTR of other genes, as revealed by RNA sequencing. It was found that PKZ18-22 has a wider range of biofilm-inhibiting properties and is 10 times more effective than frequently used antibiotics such as vancomycin [ 72 ]. Additionally, the very low levels of resistance to PKZ18 analogs supports the specific binding of them on different T-boxes and represents attractive small-molecule antibacterial drugs for future research and clinical use due to their diversified T-box targets, their minimal occurrences of resistance and their synergy with other antibiotics [ 71 ].…”

Antibiotic-free antimicrobial poly (methyl methacrylate) bone cements: A state-of-the-art review

“…Third, there are number of novel antimicrobial materials that should be investigated for their suitability to be formulated into a suitable form to be used as additives for an AFAMBC. Examples of materials that could be added to the powder of a plain cement are a quorum-sensing inhibitor drug[ 113 ], Ti-doped ZnO[ 114 ], nano-GO nanosheets[ 115 ], selenium nanoparticles[ 116 ], Ag-nanoparticle-reduced GO nanocomposite[ 117 ], chitosan hybrid nanoparticles[ 118 ], a Cu cluster molecule[ 119 ], powder prepared from extract from a Tunisian lichen[ 120 ], Yb-doped ZnO nanoparticles[ 121 ], and an analog of PKZ18 (PKZ18-22), a molecule that has been shown to block growth of antibiotic-resistant S. aureus in biofilm[ 122 ]. Examples of materials that could be added to the liquid of a plain cement are benzothiazole or one of its derivatives[ 123 , 124 ] and a natural antimicrobial agent (such as extract of Salvadora persica , Olea europaea , and Ficus carcia leaves[ 125 ] or biosynthesized ZnO nanoflowers[ 126 ]).…”

Targeted Anti-Biofilm Therapy: Dissecting Targets in the Biofilm Life Cycle

“…In addition to the advantages of directly disintegrating biofilms, it may also directly shadow the dormant cells or newly dividing cells, leading to unique therapeutic effects [ 232 ]. Thorsten M. Seyler et al reported a derivative of PKZ18 (PKZ18-22) for the first time, which can selectively target Gram-positive bacteria [ 233 ]. CRISPR interference (CRISPRi) was also one of the main technologies developed in the field of anti-infection [ 234 ].…”