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Methicillin-resistant Staphylococcus aureus (MRSA) infections present a serious challenge because of the emergence of resistance to numerous conventional antibiotics. Due to their unique mode of action, antimicrobial peptides are novel alternatives to traditional antibiotics for tackling the issue of bacterial multidrug resistance. Herein, we investigated the antibacterial activity of two short novel peptides (WR12, a 12 residue peptide composed exclusively of arginine and tryptophan, and D-IK8, an eight residue β-sheet peptide) against multidrug resistant staphylococci. In vitro , both peptides exhibited good antibacterial activity against MRSA, vancomycin-resistant S. aureus , linezolid-resistant S. aureus , and methicillin-resistant S. epidermidis . WR12 and D-IK8 were able to eradicate persisters, MRSA in stationary growth phase, and showed significant clearance of intracellular MRSA in comparison to both vancomycin and linezolid. In vivo , topical WR12 and D-IK8 significantly reduced both the bacterial load and the levels of the pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in MRSA-infected skin lesions. Moreover, both peptides disrupted established in vitro biofilms of S. aureus and S. epidermidis significantly more so than traditional antimicrobials tested. Taken together, these results support the potential of WR12 and D-IK8 to be used as a topical antimicrobial agent for the treatment of staphylococcal skin infections.

Clostridioides difficile infection is a global health threat and remains the primary cause of hospital-acquired infections worldwide. The burgeoning incidence and severity of infections coupled with high rates of recurrence have created an urgent need for novel therapeutics. Here, we report a novel natural product scaffold as a potential anticlostridial lead with antivirulence properties and potent activity both in vitro and in vivo . A whole cell phenotypic screening of 1,000 purified natural products identified 6 compounds with potent activity against C . difficile (minimum inhibitory concentration (MIC) range from 0.03 to 2 μg/ml). All these 6 compounds were non-toxic to human colorectal cells. The natural product compounds also inhibited the production of key toxins, TcdA and TcdB, the key virulence determinants of C . difficile infection pathology. Additionally, the compounds exhibited rapid bactericidal activity and were superior to the standard-of-care antibiotic vancomycin, in reducing a high inoculum of C . difficile in vitro . Furthermore, a murine model of C . difficile infection revealed that compound NP-003875 conferred 100% protection to the infected mice from clinical manifestations of the disease. Collectively, the current study lays the foundation for further investigation of the natural product NP-003875 as a potential therapeutic choice for C . difficile infection.

Accelerating growth and global expansion of antimicrobial resistance has deepened the need for discovery of novel antimicrobial agents. Antimicrobial peptides have clear advantages over conventional antibiotics which include slower emergence of resistance, broad-spectrum antibiofilm activity, and the ability to favourably modulate the host immune response. Broad bacterial susceptibility to antimicrobial peptides offers an additional tool to expand knowledge about the evolution of antimicrobial resistance. Structural and functional limitations, combined with a stricter regulatory environment, have hampered the clinical translation of antimicrobial peptides as potential therapeutic agents. Existing computational and experimental tools attempt to ease the preclinical and clinical development of antimicrobial peptides as novel therapeutics. This Review identifies the benefits, challenges, and opportunities of using antimicrobial peptides against multidrug-resistant pathogens, highlights advances in the deployment of novel promising antimicrobial peptides, and underlines the needs and priorities in designing focused development strategies taking into account the most advanced tools available.

Antimicrobial peptides (AMPs) represent a promising therapeutic alternative for the treatment of antibiotic-resistant bacterial infections. The present study investigates the antimicrobial activity of new, rationally-designed derivatives of a short α-helical peptide, RR. From the peptides designed, RR4 and its D-enantiomer, D-RR4, emerged as the most potent analogues with a more than 32-fold improvement in antimicrobial activity observed against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii . Remarkably, D-RR4 demonstrated potent activity against colistin-resistant strains of P. aeruginosa (isolated from cystic fibrosis patients) indicating a potential therapeutic advantage of this peptide over several AMPs. In contrast to many natural AMPs, D-RR4 retained its activity under challenging physiological conditions (high salts, serum, and acidic pH). Furthermore, D-RR4 was more capable of disrupting P. aeruginosa and A. baumannii biofilms when compared to conventional antibiotics. Of note, D-RR4 was able to bind to lipopolysaccharide to reduce the endotoxin-induced proinflammatory cytokine response in macrophages. Finally, D-RR4 protected Caenorhabditis elegans from lethal infections of P . aeruginosa and A . baumannii and enhanced the activity of colistin in vivo against colistin-resistant P . aeruginosa .

Candida auris is an invasive fungal pathogen, representing a global public health threat. It is characterized by high mortality rates among infected individuals, significant antifungal resistance, and a remarkable ability to persist in healthcare environments. While amphotericin B is one of the most powerful antifungal agents for treating Candida infections, approximately 30% of C. auris isolates demonstrate resistance to it. Thus, the development of novel antifungal therapies is vital for tackling its life-threatening infections. In this study, we identified four HIV protease inhibitors (atazanavir, saquinavir, lopinavir and ritonavir) as strong potentiators of amphotericin B against C. auris . A synergistic effect between HIV protease inhibitors and amphotericin B was observed against 15 C. auris isolates with fractional inhibitory concentration index (FICI) ranging from 0.09 to 0.50. Additionally, the combinations between HIV protease inhibitors and amphotericin B showed fungicidal effect, significantly reducing the viable cell count in the time-kill assay within 6 hours. Furthermore, the combinations inhibited biofilm formation of C. auris by 60–75% and exhibited a remarkable suppression of C. albicans hyphae. The in vivo treatment with HIV protease inhibitors combined with amphotericin B resulted in a significant reduction of C. auris colony-forming units (CFU) by 1.7–2.6 Log 10 in the C. elegans model. These findings suggest that HIV protease inhibitors, in combination with amphotericin B, are promising candidates for the development of novel antifungal drugs to treat Candida infections.

Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus , including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections.

Cryptococcosis is a fungal infection that is becoming increasingly prevalent worldwide, particularly among individuals with compromised immune systems, such as HIV patients. Amphotericin B (AmB) is the first-line treatment mainly combined with flucytosine. The scarcity and the prohibitive cost of this regimen urge the use of fluconazole as an alternative, leading to increased rates of treatment failure and relapses. Therefore, there is a critical need for efficient and cost-effective therapy to enhance the efficacy of AmB. In this study, we evaluated the efficacy of the HIV protease inhibitors (PIs) to synergize the activity of AmB in the treatment of cryptococcosis. Five PIs (ritonavir, atazanavir, saquinavir, lopinavir, and nelfinavir) were found to synergistically potentiate the killing activity of AmB against Cryptococcus strains with ƩFICI ranging between 0.09 and 0.5 against 20 clinical isolates. This synergistic activity was further confirmed in a time-kill assay, where different AmB/PIs combinations exhibited fungicidal activity within 24 hrs. Additionally, PIs in combination with AmB exhibited an extended post-antifungal effect on treated cryptococcal cells for approximately 10 hrs compared to 4 hours with AmB alone. This promising activity against cryptococcal cells did not exhibit increased cytotoxicity towards treated kidney cells, ruling out the risk of drug combination-induced nephrotoxicity. Finally, we evaluated the efficacy of AmB/PIs combinations in the Caenorhabditis elegans model of cryptococcosis, where these combinations significantly reduced the fungal burden of the treated nematodes by approximately 2.44 Log10 CFU (92.4%) compared to the untreated worms and 1.40 Log10 ((39.4%) compared to AmB alone. The cost-effectiveness and accessibility of PIs in resource-limited geographical areas compared to other antifungal agents, such as flucytosine, make them an appealing choice for combination therapy.

The emergence of vancomycin-resistant Enterococcus (VRE) has posed a significant global health threat, especially in healthcare settings where treatment options are increasingly limited due to rising antibiotic resistance. Maslinic acid, a naturally occurring pentacyclic triterpene found in olives, is known for its diverse biological activities, including anti-inflammatory, anticancer, antioxidant, and antimicrobial effects. In this study, we investigated the antibacterial and antibiofilm potential of maslinic acid against VRE. Initial screening identified maslinic acid as a potent hit, with minimum inhibitory concentrations (MICs) ranging from 4 to 8 µg/mL across 13 clinical enterococcal isolates, including multidrug-resistant strains. Time-kill assays demonstrated bacteriostatic activity comparable to linezolid, while cytotoxicity and hemolysis assays confirmed its safety in mammalian cells. Furthermore, maslinic acid disrupted established Enterococcus faecalis biofilms by approximately 50%, whereas linezolid was not effective against biofilms. Notably, maslinic acid significantly reduced bacterial burden in a Caenorhabditis elegans infection model by 80%, outperforming linezolid. These findings highlight maslinic acid as a promising candidate for the development of new therapies targeting VRE, with the added advantage of antibiofilm activity and a favorable safety profile.

Aspergillus fumigatus is a widely distributed pathogen responsible for severe infections, particularly in immunocompromised individuals. Triazoles are the primary treatments options for Aspergillus infections; however, the emergence of acquired resistance to this antifungal class is becoming a growing concern. In this study, we investigated the potential of the antiviral drug, lopinavir (LPV) to restore the susceptibility of A . fumigatus strains to a set of azoles, while also reducing the required azole dosage for treatment of susceptible isolates. The combination of LPV with either itraconazole (ITC) or posaconazole (POS) demonstrated potent synergistic interactions against 16 out of 23 (~70%) and 21 out of 23 (~91%) A . fumigatus isolates, respectively. Moreover, the combination showed synergistic activity against other clinically important Aspergillus species, including A . niger , A . flavus , and A . brasiliensis . The fractional inhibitory concentration index (FICI) for the combinations ranged from 0.18 to 0.313 for ITC and 0.091 to 0.313 for POS, indicating strong synergistic effects. Further investigation revealed that efflux pump inhibition contributed to the synergy observed between azole and LPV. Morphological examination of the fungal cells subjected to this combinational therapy at sub-inhibitory doses showed the presence of carbohydrate granules/patches. The identification of LPV as a promising adjunct therapy holds promise for addressing the emerging challenge of azole resistance in Aspergillus species and improving treatment outcomes for patients.

Clostridioides difficile is the leading cause of nosocomial infections and a worldwide urgent public health threat. Without doubt, there is an urgent need for new effective anticlostridial agents due to the increasing incidence and severity of C. difficile infection (CDI). The aim of the present study is to investigate the in vivo efficacy of auranofin (rheumatoid arthritis FDA-approved drug) in a CDI mouse model and establish an adequate dosage for treatment. The effects of increased C. difficile inoculum, and pre-exposure to simulated gastric intestinal fluid (SGF) and simulated intestinal fluid (SIF), on the antibacterial activity of auranofin were investigated. Auranofin’s in vitro antibacterial activity was stable in the presence of high bacterial inoculum size compared to vancomycin and fidaxomicin. Moreover, it maintained its anti- C. difficile activity after being exposed to SGF and SIF. Upon testing in a CDI mouse model, auranofin at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) significantly protected mice against CDI with 100% and 80% survival, respectively. Most importantly, auranofin (0.125 mg/kg and 0.25 mg/kg) significantly prevented CDI recurrence when compared with vancomycin. Collectively, these results indicate that auranofin could potentially provide an effective, safe and quick supplement to the current approaches for treating CDI.