A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens
The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiv...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-02-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/13/3/209 |
| _version_ | 1797242329183027200 |
|---|---|
| author | Eric J. Bryan Qi Qiao Yuxuan Wang Jacques Y. Roberge Edmond J. LaVoie Daniel S. Pilch |
| author_facet | Eric J. Bryan Qi Qiao Yuxuan Wang Jacques Y. Roberge Edmond J. LaVoie Daniel S. Pilch |
| author_sort | Eric J. Bryan |
| collection | DOAJ |
| description | The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (<b>RUP4</b>) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe<sup>3+</sup>) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that <b>RUP4</b> is active against both <i>Klebsiella pneumoniae</i> and <i>Acinetobacter baumannii</i>, with this activity being dependent on direct Fe<sup>3+</sup> chelation and enhanced under Fe<sup>3+</sup>-limiting conditions. Genetic deletion studies in <i>K. pneumoniae</i> reveal that <b>RUP4</b> gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that <b>RUP4</b> exhibits bactericidal synergy against <i>K. pneumoniae</i> when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting β-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe<sup>3+</sup>-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance. |
| first_indexed | 2024-04-24T18:37:29Z |
| format | Article |
| id | doaj.art-3695e2f711df4ee8bc9ee482638de326 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-04-24T18:37:29Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-3695e2f711df4ee8bc9ee482638de3262024-03-27T13:18:04ZengMDPI AGAntibiotics2079-63822024-02-0113320910.3390/antibiotics13030209A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial PathogensEric J. Bryan0Qi Qiao1Yuxuan Wang2Jacques Y. Roberge3Edmond J. LaVoie4Daniel S. Pilch5Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USADepartment of Molecular Design and Synthesis, Rutgers University Biomedical Innovation Cores, Piscataway, NJ 08854, USADepartment of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USADepartment of Molecular Design and Synthesis, Rutgers University Biomedical Innovation Cores, Piscataway, NJ 08854, USADepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USADepartment of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USAThe global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (<b>RUP4</b>) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe<sup>3+</sup>) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that <b>RUP4</b> is active against both <i>Klebsiella pneumoniae</i> and <i>Acinetobacter baumannii</i>, with this activity being dependent on direct Fe<sup>3+</sup> chelation and enhanced under Fe<sup>3+</sup>-limiting conditions. Genetic deletion studies in <i>K. pneumoniae</i> reveal that <b>RUP4</b> gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that <b>RUP4</b> exhibits bactericidal synergy against <i>K. pneumoniae</i> when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting β-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe<sup>3+</sup>-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance.https://www.mdpi.com/2079-6382/13/3/209<i>Klebsiella pneumoniae</i><i>Acinetobacter baumannii</i>antibiotic-siderophore conjugateantibiotic uptakeFtsZ inhibitor-antibiotic synergy |
| spellingShingle | Eric J. Bryan Qi Qiao Yuxuan Wang Jacques Y. Roberge Edmond J. LaVoie Daniel S. Pilch A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens Antibiotics <i>Klebsiella pneumoniae</i> <i>Acinetobacter baumannii</i> antibiotic-siderophore conjugate antibiotic uptake FtsZ inhibitor-antibiotic synergy |
| title | A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens |
| title_full | A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens |
| title_fullStr | A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens |
| title_full_unstemmed | A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens |
| title_short | A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens |
| title_sort | ftsz inhibitor that can utilize siderophore ferric iron uptake transporter systems for activity against gram negative bacterial pathogens |
| topic | <i>Klebsiella pneumoniae</i> <i>Acinetobacter baumannii</i> antibiotic-siderophore conjugate antibiotic uptake FtsZ inhibitor-antibiotic synergy |
| url | https://www.mdpi.com/2079-6382/13/3/209 |
| work_keys_str_mv | AT ericjbryan aftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT qiqiao aftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT yuxuanwang aftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT jacquesyroberge aftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT edmondjlavoie aftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT danielspilch aftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT ericjbryan ftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT qiqiao ftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT yuxuanwang ftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT jacquesyroberge ftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT edmondjlavoie ftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens AT danielspilch ftszinhibitorthatcanutilizesiderophoreferricironuptaketransportersystemsforactivityagainstgramnegativebacterialpathogens |