TY - JOUR
T1 - Polyether Ionophore Antibiotics Target Drug-Resistant Clinical Isolates, Persister Cells, and Biofilms
AU - Wollesen, Malene
AU - Mikkelsen, Kasper
AU - Tvilum, Marie Selch
AU - Vestergaard, Martin
AU - Wang, Mikala
AU - Meyer, Rikke L
AU - Ingmer, Hanne
AU - Poulsen, Thomas
AU - Tørring, Thomas
PY - 2023/8
Y1 - 2023/8
N2 - Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture (e.g., as anti-coccidiostats) and have potent antibacterial activity, they are not currently being pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they significantly differ in structure; for this reason, how their structure and activity are related remains unclear. To determine whether certain members of the family constitute particularly interesting springboards for in-depth investigations and future synthetic optimization, we conducted a systematic comparative study of eight different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds' effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development. IMPORTANCE Polyether ionophores are complex natural products used in agriculture as anti-coccidiostats in poultry and as growth promoters in cattle, although their precise mechanism is not understood. They are widely regarded as antimicrobials against Gram-positive bacteria and protozoa, but fear of toxicity has so far prevented their use in humans. We show that ionophores generally have very different effects on Staphylococcus aureus, both in standard assays and in more complex systems such as bacterial biofilms and persister cell populations. This will allow us to focus on the most interesting compounds for future in-depth investigations and synthetic optimizations.
AB - Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture (e.g., as anti-coccidiostats) and have potent antibacterial activity, they are not currently being pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they significantly differ in structure; for this reason, how their structure and activity are related remains unclear. To determine whether certain members of the family constitute particularly interesting springboards for in-depth investigations and future synthetic optimization, we conducted a systematic comparative study of eight different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds' effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development. IMPORTANCE Polyether ionophores are complex natural products used in agriculture as anti-coccidiostats in poultry and as growth promoters in cattle, although their precise mechanism is not understood. They are widely regarded as antimicrobials against Gram-positive bacteria and protozoa, but fear of toxicity has so far prevented their use in humans. We show that ionophores generally have very different effects on Staphylococcus aureus, both in standard assays and in more complex systems such as bacterial biofilms and persister cell populations. This will allow us to focus on the most interesting compounds for future in-depth investigations and synthetic optimizations.
KW - Animals
KW - Anti-Bacterial Agents/therapeutic use
KW - Anti-Infective Agents/pharmacology
KW - Biofilms
KW - Cattle
KW - Gram-Positive Bacteria
KW - Humans
KW - Ionophores/pharmacology
KW - Microbial Sensitivity Tests
KW - ionophore
KW - antimicrobial resistance
KW - biofilm
KW - natural antimicrobial products
KW - antibiotics
KW - Staphylococcus aureus
KW - persister cells
UR - http://www.scopus.com/inward/record.url?scp=85172320093&partnerID=8YFLogxK
U2 - 10.1128/spectrum.00625-23
DO - 10.1128/spectrum.00625-23
M3 - Journal article
C2 - 37289074
SN - 2165-0497
VL - 11
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 4
M1 - e0062523
ER -