Microbial metal homeostasis involves the acquisition, transport, storage, and utilization of metal ions that serve structural, regulatory, and catalytic roles in the cell [1, 2, 3, 4]. Many bacteria and fungi live in environments where metal availability is low, which poses a challenge for obtaining the necessary concentrations of these essential nutrients. A common strategy to overcome low metal availability is the biosynthesis and deployment of metallophores, secondary metabolites that chelate metal ions with high affinity [5, 6, 7, 8, ∗9]. By providing metal nutrients (e.g., Fe, Ni, Cu, Zn, Mo), these molecules and their uptake systems are invaluable for the survival and growth of bacterial and fungal species living in diverse environments. In the canonical model of metallophore-mediated metal uptake, a metallophore binds a metal ion from the extracellular environment, and the resulting complex is recognized by a cell membrane receptor and internalized. Once inside the cell, the nutrient metal ion is released from the metallophore and utilized for various cellular processes.

Our understanding of metallophores, including their roles in acquiring various metals and their contributions to other biological phenomena, continues to expand [9,10]. For instance, the functional versatility of yersiniabactin (Ybt, Figure 1) in metal uptake was recently supported by its ability to scavenge and transport metal ions other than Fe(III), including Ni(II), Cu(II), and Zn(II) [11, 12, 13, 14, 15, 16, 17]. Additionally, as highlighted in this Current Opinion, the involvement of Ybt in quorum sensing (QS) reveals a fascinating non-canonical role for this metallophore [18].

Fundamental understanding of the biosynthesis, coordination chemistry, and uptake mechanisms of metallophores has enabled researchers to harness these molecules and their uptake pathways for various applications, including in the infectious disease space. The pressing need for new strategies to prevent and treat microbial infections has motivated efforts towards employing metallophores for therapeutic purposes. Examples include harnessing siderophores and their uptake systems in non-traditional antibacterial strategies [19, 20, 21, ∗22]. Along these lines, a recent study described herein reveals that Zn(II) and Co(II) complexes of the fungal metallophore aspergillomarasmine A (AMA, Figure 1) can interfere with bacterial Ni uptake machinery, thereby reducing cellular Ni levels and virulence [23].

Since the discovery of the first metallophores ∼75 years ago, hundreds of others have been and continue to be identified [5,9,24,25]. In general, metallophores bind and transport first and second-row transition metal ions such as Fe(III), Ni(II), Cu(II), Zn(II), and Mo(IV) [2,9,24]. Some bacteria utilize lanthanide (Ln) ions as enzyme cofactors [26, 27, 28], and the community has speculated that Ln-binding metabolites akin to Fe(III)-scavenging siderophores exist. The third vignette in this review focuses on the recent identification and isolation of methylolanthanin (MLL, Figure 1) from Methylobacterium extorquens AM1 cultures, which is biosynthesized in response to Ln availability and was shown to ferry Nd into the cell [29].

By summarizing these recent metallophore studies, we aim to highlight how the field continues to broaden as researchers reveal non-canonical roles for well-known molecules, employ naturally occurring metallophores for novel applications, and discover new metal-sequestering natural products.