The emergence of drug-resistant fungi poses a major threat to human health. Despite advances in preventive, diagnostic, and therapeutic interventions, resistant fungal infections continue to cause significant morbidity and mortality in patients with compromised immunity, underscoring the urgent need for new antifungal agents. In this article, we review the challenges associated with identifying broad-spectrum antifungal drugs and highlight novel targets that could enhance the armamentarium of agents available to treat drug-resistant invasive fungal infections.

Introduction: The emergence of multidrug-resistant bacterial pathogens has led to a global public health emergency and novel therapeutic options and drug-delivery systems are urgently needed. Cefiderocol is a siderophore cephalosporin antibiotic that has recently been developed to combat a variety of bacterial pathogens, including β-lactam- and carbapenem-resistant organisms. Areas covered: This paper provides an overview of the mutational and plasmid-mediated mechanisms of β-lactam and carbapenem resistance, the biochemical pathways of siderophores in bacterial iron metabolism, and how cefiderocol may be able to provide better targeted antimicrobial therapy that escape these drug-resistant mechanisms. We also explore the pharmacokinetics of this new compound as well as results from preclinical and clinical studies. Expert opinion: There is an urgent need for novel antimicrobial agents to address the emergence of multidrug-resistant pathogens, which are an increasing cause of morbidity and mortality worldwide. Our understanding of multidrug-resistance and bacterial biochemical pathways continues to expand, and the development of cefiderocol specifically targeting siderophore-mediated iron transport shows potential in escaping mechanisms of drug resistance. Cefiderocol, which demonstrates a favorable side effect profile, has the potential to become first-line therapy for our most aggressive and lethal multidrug-resistant Gram-negative pathogens.

Species of Scedosporium and Fusarium are considered emerging opportunistic pathogens, causing invasive fungal diseases in humans that are known as scedosporiosis and fusariosis, respectively. These mold infections typically affect patients with immune impairment; however, cases have been reported in otherwise healthy individuals. Clinical manifestations vary considerably, ranging from isolated superficial infection to deep-seated invasive infection—affecting multiple organs—which is often lethal. While there have been a number of advances in the detection of these infections, including the use of polymerase chain reaction (PCR) and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS), diagnosis is often delayed, leading to substantial morbidity and mortality. Although the optimal therapy is controversial, there have also been notable advances in the treatment of these diseases, which often depend on a combination of antifungal therapy, reversal of immunosuppression, and in some cases, surgical resection. In this paper, we review these advances and examine how the management of scedosporiosis and fusariosis may change in the near future.

Although uncommon in children, fungal infections of the central nervous system can be devastating and difficult to treat. A better understanding of basic mycologic, immunologic, and pharmacologic processes has led to important advances in the diagnosis and management of these diseases, but their mortality rates remain unacceptably high. In this focused review, we examine the epidemiology and clinical features of the most common fungal pathogens of the central nervous system in children and explore recent advances in diagnosis and antifungal therapy.

Discovering new drugs for treatment of invasive fungal infections is an enduring challenge. There are only three major classes of antifungal agents, and no new class has been introduced into clinical practice in more than a decade. However, recent advances in our understanding of the fungal life cycle, functional genomics, proteomics, and gene mapping have enabled the identification of new drug targets to treat these potentially deadly infections. In this paper, we examine amino acid transport mechanisms and metabolism as potential drug targets to treat invasive fungal infections, including pathogenic yeasts, such as species of Candida and Cryptococcus, as well as molds, such as Aspergillus fumigatus. We also explore the mechanisms by which amino acids may be exploited to identify novel drug targets and review potential hurdles to bringing this approach into clinical practice.