The rapid increase in antibiotic resistance presents a dire situation necessitating the need for alternative therapeutic agents. Among the current alternative therapies, phage therapy (PT) is promising. This review extensively summarizes preclinical PT approaches in various in-vivo models. PT has been evaluated in several recent clinical trials. However, there are still several unanswered concerns due to a lack of appropriate regulation and pharmacokinetic data regarding the application of phages in human therapeutic procedures. In this review, we also presented the current state of PT and considered how animal models can be used to adapt these therapies for humans. The development of realistic solutions to circumvent these constraints is critical for advancing this technology.

Hospital-acquired infections (HAIs) pose a significant risk to global health, impacting millions of individuals globally. These infections have increased rates of morbidity and mortality due to the prevalence of widespread antimicrobial resistance (AMR). Graphene-based nanoparticles (GBNs) are known to possess extensive antimicrobial properties by inflicting damage to the cell membrane, suppressing virulence, and inhibiting microbial biofilms. Developing alternative therapies for HAIs and addressing AMR can be made easier and more affordable by combining nanoparticles with medicinal plants harboring antimicrobial properties. Hence, this study was undertaken to develop a novel graphene–silver nanocomposite via green synthesis using Trillium govanianum plant extract as a reducing agent. The resulting nanocomposite comprised silver nanoparticles embedded in graphene sheets. The antibacterial and antifungal properties of graphene–silver nanocomposites were investigated against several nosocomial pathogens, namely, Candida auris, Candida glabrata, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The nanocomposite displayed broad-range antimicrobial potential against the test pathogens, with minimum inhibitory concentrations (MICs) ranging between 31.25 and 125.0 µg/mL, and biofilm inhibition up to 80–96%. Moreover, nanocomposite-functionalized urinary catheters demonstrated hemocompatibility towards sheep erythrocytes and imparted anti-fouling activity to the biomaterial, while also displaying biocompatibility towards HEK 293 cells. Collectively, this investigation highlights the possible application of green-synthesized GBNs as an effective alternative to conventional antibiotics for combating multidrug-resistant pathogens.

Methicillin-resistant Staphylococcus aureus (MRSA) is a global healthcare concern. Such resistance has historically been attributed to the acquisition of mecA (or mecC), which encodes an alternative penicillin binding protein, PBP2a, with low β-lactam affinity. However, recent studies have indicated that penicillin binding protein 4 (PBP4) is also a critical determinant of S. aureus methicillin resistance, particularly among community-acquired MRSA strains. Thus, PBP4 has been considered an intriguing therapeutic target as corresponding inhibitors may restore MRSA β-lactam susceptibility. In addition to its role in antibiotic resistance, PBP4 has also recently been shown to be required for S. aureus cortical bone osteocyte lacuno-canalicular network (OLCN) invasion and colonization, providing the organism with a niche for re-occurring bone infection. From these perspectives, the development of PBP4 inhibitors may have tremendous impact as agents that both reverse methicillin resistance and inhibit the organism’s ability to cause chronic osteomyelitis. Accordingly, using a whole-cell high-throughput screen of a 30,000-member small molecule chemical library and secondary assays we identified putative S. aureus PBP4 inhibitors. Quantitative reverse transcriptase mediated PCR and PBP4 binding assays revealed that hits could be further distinguished as compounds that reduce PBP4 expression versus compounds that are likely to affect the protein’s function. We also showed that 6.25 µM (2.5 µg/mL) of the lead candidate, 9314848, reverses the organism’s PBP4-dependent MRSA phenotype and inhibits its ability to traverse Microfluidic-Silicon Membrane-Canalicular Arrays (µSiM-CA) that model the OLCN orifice. Collectively, these molecules may represent promising potential as PBP4-inhibitors that can be further developed as adjuvants for the treatment of MRSA infections and/or osteomyelitis prophylactics.