skip to main content

Explore Research Products in the NSF-PAR

Title: Exploring Titanium(IV) Complexes as Potential Antimicrobial Compounds
Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other germs, making them untreatable. The search for more combative antibiotic compounds has led researchers to explore metal-based strategies centered on perturbing the bioavailability of essential metals in microbes and examining the therapeutic potential of metal complexes. Given the limited knowledge on the application of titanium(IV), in this work, eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. The compounds were selected for evaluation because of their low cytotoxic/antiproliferative behavior against a human non-cancer cell line. At pH 7.4, these compounds vary in terms of their solution stability and ligand exchange lability; therefore, an assessment of their solution behavior provides some insight regarding the importance of the identity of the metal compound to the antimicrobial therapeutic potential. Only one compound, Ti(deferasirox)2, exhibited promising inhibitory activity against the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and minimal toxicity against human cells. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and ribonucleotide reductase is evaluated as a possible mechanism for its antibiotic effect.  more » « less
Award ID(s):
1757365
NSF-PAR ID:
10315509
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
Antibiotics
Volume:
11
Issue:
2
ISSN:
2079-6382
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ( , mSphere)
    Dunman, Paul (Ed.)
    ABSTRACT The bacterial type IV pilus (T4P) is a prominent virulence factor in many significant human pathogens, some of which have become increasingly antibiotic resistant. Antivirulence chemotherapeutics are considered a promising alternative to antibiotics because they target the disease process instead of bacterial viability. However, a roadblock to the discovery of anti-T4P compounds is the lack of a high-throughput screen (HTS) that can be implemented relatively easily and economically. Here, we describe the first HTS for the identification of inhibitors specifically against the T4P assembly ATPase PilB in vitro . Chloracidobacterium thermophilum PilB ( Ct PilB) had been demonstrated to have robust ATPase activity and the ability to bind its expected ligands in vitro. We utilized Ct PilB and MANT-ATP, a fluorescent ATP analog, to develop a binding assay and adapted it for an HTS. As a proof of principle, we performed a pilot screen with a small compound library of kinase inhibitors and identified quercetin as a PilB inhibitor in vitro . Using Myxococcus xanthus as a model bacterium, we found quercetin to reduce its T4P-dependent motility and T4P assembly in vivo. These results validated our HTS as effective in identifying PilB inhibitors. This assay may prove valuable in seeking leads for the development of antivirulence chemotherapeutics against PilB, an essential and universal component of all bacterial T4P systems. IMPORTANCE Many bacterial pathogens use their type IV pili (T4P) to facilitate and maintain infection of a human host. Small chemical compounds that inhibit the production or assembly of T4P hold promise in the treatment and prevention of infections, especially in the era of increasing threats from antibiotic-resistant bacteria. However, few chemicals are known to have inhibitory or anti-T4P activity. Their identification has not been easy due to the lack of a method for the screening of compound collections or libraries on a large scale. Here, we report the development of an assay that can be scaled up to screen compound libraries for inhibitors of a critical T4P assembly protein. We further demonstrate that it is feasible to use whole cells to examine potential inhibitors for their activity against T4P assembly in a bacterium. 
    more » « less
  2. ; ; ; ; ; ; ; ; ( , Marine Drugs)
    null (Ed.)
    Among the different tools to address the antibiotic resistance crisis, bioprospecting in complex uncharted habitats to detect novel microorganisms putatively producing original antimicrobial compounds can definitely increase the current therapeutic arsenal of antibiotics. Fungi from numerous habitats have been widely screened for their ability to express specific biosynthetic gene clusters (BGCs) involved in the synthesis of antimicrobial compounds. Here, a collection of unique 75 deep oceanic crust fungi was screened to evaluate their biotechnological potential through the prism of their antimicrobial activity using a polyphasic approach. After a first genetic screening to detect specific BGCs, a second step consisted of an antimicrobial screening that tested the most promising isolates against 11 microbial targets. Here, 12 fungal isolates showed at least one antibacterial and/or antifungal activity (static or lytic) against human pathogens. This analysis also revealed that Staphylococcus aureus ATCC 25923 and Enterococcus faecalis CIP A 186 were the most impacted, followed by Pseudomonas aeruginosa ATCC 27853. A specific focus on three fungal isolates allowed us to detect interesting activity of crude extracts against multidrug-resistant Staphylococcus aureus. Finally, complementary mass spectrometry (MS)-based molecular networking analyses were performed to putatively assign the fungal metabolites and raise hypotheses to link them to the observed antimicrobial activities. 
    more » « less
  3. ; ( , Journal of Biomedical Materials Research Part A)
    Abstract

    Despite the promise of antimicrobial peptides (AMPs) as treatments for antibiotic‐resistant infections, their therapeutic efficacy is limited due to the rapid degradation and low bioavailability of AMPs. To address this, we have developed and characterized a synthetic mucus (SM) biomaterial capable of delivering LL37 AMPs and enhancing their therapeutic effect. LL37 is an AMP that exhibits a wide range of antimicrobial activity against bacteria, includingPseudomonas aeruginosa. LL37 loaded SM hydrogels demonstrated controlled release with 70%–95% of loaded LL37 over 8 h due to charge‐mediated interactions between mucins and LL37 AMPs. Compared to treatment with LL37 alone where antimicrobial activity was reduced after 3 h, LL37‐SM hydrogels inhibitedP. aeruginosa(PAO1) growth over 12 h. LL37‐SM hydrogel treatment reduced PAO1 viability over 6 h whereas a rebound in bacterial growth was observed when treated with LL37 only. These data demonstrate LL37‐SM hydrogels enhance antimicrobial activity by preserving LL37 AMP activity and bioavailability. Overall, this work establishes SM biomaterials as a platform for enhanced AMP delivery for antimicrobial applications.

     
    more » « less
  4. ; ; ; ; ; ; ; ( , Microbiology Spectrum)
    Visca, Paolo (Ed.)
    ABSTRACT With the pressing antibiotic resistance pandemic, antivirulence has been increasingly explored as an alternative strategy against bacterial infections. The bacterial type IV pilus (T4P) is a well-documented virulence factor and an attractive target for small molecules for antivirulence purposes. The PilB ATPase is essential for T4P biogenesis because it catalyzes the assembly of monomeric pilins into the polymeric pilus filament. Here, we describe the identification of two PilB inhibitors by a high-throughput screen (HTS) in vitro and their validation as effective inhibitors of T4P assembly in vivo . We used Chloracidobacterium thermophilum PilB as a model enzyme to optimize an ATPase assay for the HTS. From a library of 2,320 compounds, benserazide and levodopa, two approved drugs for Parkinson’s disease, were identified and confirmed biochemically to be PilB inhibitors. We demonstrate that both compounds inhibited the T4P-dependent motility of the bacteria Myxoccocus xanthus and Acinetobacter nosocomialis . Additionally, benserazide and levodopa were shown to inhibit A. nosocomialis biofilm formation, a T4P-dependent process. Using M. xanthus as a model, we showed that both compounds inhibited T4P assembly in a dose-dependent manner. These results suggest that these two compounds are effective against the PilB protein in vivo. The potency of benserazide and levodopa as PilB inhibitors both in vitro and in vivo demonstrate potentials of the HTS and its two hits here for the development of anti-T4P chemotherapeutics. IMPORTANCE Many bacterial pathogens use their type IV pilus (T4P) to facilitate and maintain an infection in a human host. Small-molecule inhibitors of the production or assembly of the T4P are promising for the treatment and prevention of infections by these bacteria, especially in our fight against antibiotic-resistant pathogens. Here, we report the development and implementation of a method to identify anti-T4P chemicals from compound libraries by high-throughput screen. This led to the identification and validation of two T4P inhibitors both in the test tubes and in bacteria. The discovery and validation pipeline reported here as well as the confirmation of two anti-T4P inhibitors provide new venues and leads for the development of chemotherapeutics against antibiotic-resistant infections. 
    more » « less
  5. ; ; ; ; ; ; ; ; ; ; et al ( , Chemical Biology & Drug Design)
    Abstract

    Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug‐resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti‐tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2‐a]pyridinecarboxamide derivatives for their anti‐tuberculosis properties. These compounds were designed based on reported anti‐tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2‐a]pyridinecarboxamides (IPAs). In this series, we identified compounds15and16with excellent anti‐TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates ofMtb. Compounds15and16showed excellent activities against multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound16showed favorable pharmacokinetic properties.

     
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email