Antimicrobial resistance poses a serious threat to global health, necessitating the exploration of innovative solutions.

Bacterial infections are raising serious concern across the globe. The effectiveness of conventional antibiotics is decreasing due to global emergence of multi-drug-resistant (MDR) bacterial pathogens. This process seems to be primarily caused by an indiscriminate and inappropriate use of antibiotics in non-infected patients and in the food industry. New classes of antibiotics with different actions against MDR pathogens need to be developed urgently. In this context, this review focuses on several ways and future directions to search for the next generation of safe and effective antibiotics compounds including antimicrobial peptides, phage therapy, phytochemicals, metalloantibiotics, LPS and efflux pump inhibitors to control the infections caused by MDR pathogens.

Significance: Repair of mutagenic oxidized bases in the genome is required before replication to prevent mutations. It is unknown how such base lesions, which do not block replication, are flagged for repair in the single-stranded replicating template. We demonstrate here that the repair-initiating, S-phase–activated Nei-like (NEIL) 1 DNA glycosylase binds to but does not excise the base lesion and cleave the template DNA strand, which would lead to a lethal double-strand break. Instead, NEIL1 blocks progression of the replication fork, which then regresses to allow lesion repair. In the absence of NEIL1, the related glycosylase NEIL2 serves as a backup enzyme.

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3’-P and 5’-OH, are processed by mammalian polynucleotide kinase 3’-phosphatase (PNKP), a bifunctional enzyme with 3’-phosphatase and 5’-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14–41 to 55–82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP’s 3’ phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3’-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients’ brain. Finally, long amplicon quantitative PCR analysis of human MJD patients’ brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD. We report that human polynucleotide kinase 3’-phosphatase (PNKP), a major DNA strand break repair enzyme, stably associates with Ataxin-3 (ATXN3). This protein contains repeats of the amino acid glutamine, and the expansion of these repeats from 14–41 to 55–82 glutamines leads to a neurological disorder called Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). However, how this expansion of glutamine leads to ataxia has remained unclear. Here we show that normal ATXN3 protein stimulates, but the expanded ATXN3 inhibits, PNKP’s DNA repair activity, causing an accumulation of DNA damage. Furthermore, a SCA3 mouse model showed decreased PNKP activity, mostly in a region that is highly affected in MJD patients’ brains. Analysis of human MJD patients’ neuronal DNA showed significant accumulation of DNA strand breaks. Collectively, the accumulation of DNA damage due to decreased PNKP repair activity is likely to induce neuronal cell death, a hallmark of SCA3/MJD pathogenesis.

Long-term treatment with several conventional antibiotics can cause harmful side effects that can be alleviated by antioxidant therapy. Phenolic compounds (PCs) are the best source of antioxidants, and to identify the most suitable polyphenols for use as a supportive supplement during antibiotic therapy, this study screened a series of PCs to establish their antibacterial potential, including their biofilm and β-lactamase inhibition activity. Several PCs were tested for antibacterial activity against Staphylococcus epidermidis and Pseudomonas aeruginosa. Among them, tannic acid, epigallocatechin gallate, rutin, and eugenol showed the highest antibacterial activity. Epigallocatechin gallate, tannic acid, quercetin, and epicatechin inhibited a significant level of β-lactamase activity. Tannic acid and epigallocatechin gallate presented the highest β-lactamase inhibition potential in both in vitro and in silico analysis. In the present work, these two PCs were the most active agents, presenting both antibacterial activity and β-lactamase and biofilm inhibition ability.