Repurposing Cryptosporidium Inosine 5′-Monophosphate Dehydrogenase Inhibitors as Potential Antibacterial Agents

Abstract

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. IMPDH is a target for immunosuppressive, antiviral, and anticancer drugs, but, as of yet, has not been exploited for antimicrobial therapy. We have previously reported potent inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum (CpIMPDH). Many pathogenic bacteria, including Bacillus anthracis, Staphylococcus aureus, and Listeria monocytogenes, contain IMPDHs that should also be inhibited by these compounds. Herein, we present the structure-activity relationships for the inhibition of B. anthracis IMPDH (BaIMPDH) and antibacterial activity of 140 compounds from five structurally distinct compound series. Many potent inhibitors of BaIMPDH were identified (78% with IC50 ≤ 1 μM). Four compounds had minimum inhibitory concentrations (MIC) of less than 2 μM against B. anthracis Sterne 770. These compounds also displayed antibacterial activity against S. aureus and L. monocytogenes.

Inosine 5′-Monophosphate Dehydrogenase Inhibitors as Antimicrobial Agents: Recent Progress and Future Perspectives

“…X-ray crystal structures of CpIMPDH inhibitors with parasite and bacterial IMPDHs have defined the structural determinants of inhibition. In brief, CpIMPDH inhibitors typically consist of two aromatic groups separated by a linker ( Figure 4A) [8]. The transformations occurring during the IMPDH catalytic cycle makes inhibitor design really challenging due to failure in predicting the structural consequences of inhibitor binding [12].…”

“…Several bacterial pathogens, including Mtb, S. aureus, K. pneumoniae, B. anthracis, Helicobacter pylori, Streptococcus pyogenes, Clostridium perfringens, and Campylobacter jejuni but, not in Vibrio cholera possess this motif [26]. There is cross-reactivity among CpIMPDH, BaIMPDH and IMPDHs from few Gram-positive bacteria with reference to the inhibitors [8].…”

“…In an effort to develop broad-spectrum antibiotics, repurposing of CpIMPDH inhibitors was reported recently [8]. The hypothesis was based on the observation that IMPDHs are present in many pathogenic bacteria, including B. anthracis, S. aureus and L. monocytogenes and CpIMPDH inhibitors should be able to inhibit bacterial IMPDHs.…”

“…The discovery and development of novel anticryptosporidium therapeutics have been held back by the poor experimental tractability of this pathogen [5]. Overall, strategies such as development of newer, broad-spectrum antibiotics acting at novel molecular targets, newer vaccines and unconventional antimicrobial therapy are being tried for confronting antibiotic resistance [6][7][8]. Of the several validated targets, inosine 5Arasu -monophosphate dehydrogenase (IMPDH) is a potential target for the development of antimicrobial (e.g., antibacterial, antiviral, antifungal, antimycobacterial and anti-protozaon parasitic) agents.…”

Development of novel anti-infective drugs targeting microbial proteins

“…Out of these, MPA and mizoribine have also shown activity against fungal IMPDH, however, they cannot be used for treatment of fungal infections due to their immunosuppressant activity (90,111,112) which would be counterproductive in the case of a fungal infection. Apart from these drugs, several inhibitors targeting human, bacterial and parasitic IMPDH are currently under investigation or in development (113)(114)(115)(116)(117)(118)(119)(120). In conclusion, one of the major challenges is to design and develop inhibitors selective for C. neoformans IMPDH, which do not inhibit both human IMPDH isoforms, type I and type II.…”