Abstract
The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a nontoxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms. Compound PcephPT (phenylacetamido-cephem-pyrithione) contains a cephalosporin core linked to 2-mercaptopyridine N-oxide (pyrithione) via one of its metal-chelating atoms, which minimizes its preactivation interaction with metal ions and its cytotoxicity. Spectroscopic and chromatographic assays indicate that PcephPT releases pyrithione in the presence of β-lactamase-producing bacteria. The prochelator shows enhanced antibacterial activity against strains expressing β-lactamases, with bactericidal efficacy improved by the presence of low-micromolar copper in the growth medium. Metal analysis shows that cell-associated copper accumulation by the prochelator is significantly lower than that induced by pyrithione itself, suggesting that the location of pyrithione release influences biological outcomes. Low-micromolar (4-8 μg/mL) minimum inhibitory concentration (MIC) values of PcephPT in ceftriaxone-resistant bacteria compared with median lethal dose (LD50) values greater than 250 μM in mammalian cells suggests favorable selectivity. Further investigation into the mechanisms of prochelators will provide insight for the design of new antibacterial agents that manipulate cellular metallobiology as a strategy against infection.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1019-1029 |
| Number of pages | 11 |
| Journal | ACS Infectious Diseases |
| Volume | 4 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 8 2018 |
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Keywords
- antibacterial
- chelation
- copper
- prochelator
- resistance
- β-lactamase
ASJC Scopus subject areas
- Infectious Diseases
Cite this
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Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria. / Zaengle-Barone, Jacqueline M.; Jackson, Abigail C.; Besse, David M.; Becken, Bradford; Arshad, Mehreen; Seed, Patrick Casey; Franz, Katherine J.
In: ACS Infectious Diseases, Vol. 4, No. 6, 08.06.2018, p. 1019-1029.Research output: Contribution to journal › Article
TY - JOUR
T1 - Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria
AU - Zaengle-Barone, Jacqueline M.
AU - Jackson, Abigail C.
AU - Besse, David M.
AU - Becken, Bradford
AU - Arshad, Mehreen
AU - Seed, Patrick Casey
AU - Franz, Katherine J.
PY - 2018/6/8
Y1 - 2018/6/8
N2 - The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a nontoxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms. Compound PcephPT (phenylacetamido-cephem-pyrithione) contains a cephalosporin core linked to 2-mercaptopyridine N-oxide (pyrithione) via one of its metal-chelating atoms, which minimizes its preactivation interaction with metal ions and its cytotoxicity. Spectroscopic and chromatographic assays indicate that PcephPT releases pyrithione in the presence of β-lactamase-producing bacteria. The prochelator shows enhanced antibacterial activity against strains expressing β-lactamases, with bactericidal efficacy improved by the presence of low-micromolar copper in the growth medium. Metal analysis shows that cell-associated copper accumulation by the prochelator is significantly lower than that induced by pyrithione itself, suggesting that the location of pyrithione release influences biological outcomes. Low-micromolar (4-8 μg/mL) minimum inhibitory concentration (MIC) values of PcephPT in ceftriaxone-resistant bacteria compared with median lethal dose (LD50) values greater than 250 μM in mammalian cells suggests favorable selectivity. Further investigation into the mechanisms of prochelators will provide insight for the design of new antibacterial agents that manipulate cellular metallobiology as a strategy against infection.
AB - The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a nontoxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms. Compound PcephPT (phenylacetamido-cephem-pyrithione) contains a cephalosporin core linked to 2-mercaptopyridine N-oxide (pyrithione) via one of its metal-chelating atoms, which minimizes its preactivation interaction with metal ions and its cytotoxicity. Spectroscopic and chromatographic assays indicate that PcephPT releases pyrithione in the presence of β-lactamase-producing bacteria. The prochelator shows enhanced antibacterial activity against strains expressing β-lactamases, with bactericidal efficacy improved by the presence of low-micromolar copper in the growth medium. Metal analysis shows that cell-associated copper accumulation by the prochelator is significantly lower than that induced by pyrithione itself, suggesting that the location of pyrithione release influences biological outcomes. Low-micromolar (4-8 μg/mL) minimum inhibitory concentration (MIC) values of PcephPT in ceftriaxone-resistant bacteria compared with median lethal dose (LD50) values greater than 250 μM in mammalian cells suggests favorable selectivity. Further investigation into the mechanisms of prochelators will provide insight for the design of new antibacterial agents that manipulate cellular metallobiology as a strategy against infection.
KW - antibacterial
KW - chelation
KW - copper
KW - prochelator
KW - resistance
KW - β-lactamase
UR - http://www.scopus.com/inward/record.url?scp=85048301485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048301485&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.8b00037
DO - 10.1021/acsinfecdis.8b00037
M3 - Article
C2 - 29557647
AN - SCOPUS:85048301485
VL - 4
SP - 1019
EP - 1029
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
SN - 2373-8227
IS - 6
ER -