Genomic studies and experiments with permeability-deficient
strains
have revealed a variety of biological targets that can be engaged
to kill Gram-negative bacteria. However, the formidable outer membrane
and promiscuous efflux pumps of these pathogens prevent many candidate
antibiotics from reaching these targets. One such promising target
is the enzyme FabI, which catalyzes the rate-determining step in bacterial
fatty acid biosynthesis. Notably, FabI inhibitors have advanced to
clinical trials for Staphylococcus aureus infections
but not for infections caused by Gram-negative bacteria. Here, we
synthesize a suite of FabI inhibitors whose structures fit permeation
rules for Gram-negative bacteria and leverage activity against a challenging
panel of Gram-negative clinical isolates as a filter for advancement.
The compound to emerge, called fabimycin, has impressive activity
against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter
baumannii, and does not kill commensal bacteria. X-ray structures
of fabimycin in complex with FabI provide molecular insights into
the inhibition. Fabimycin demonstrates activity in multiple mouse
models of infection caused by Gram-negative bacteria, including a
challenging urinary tract infection model. Fabimycin has translational
promise, and its discovery provides additional evidence that antibiotics
can be systematically modified to accumulate in Gram-negative bacteria
and kill these problematic pathogens.
Glioblastoma (GBM) is the most lethal primary brain tumor. Currently, frontline treatment for primary GBM includes the DNA-methylating drug temozolomide (TMZ, of the imidazotetrazine class), while the optimal treatment for recurrent GBM remains under investigation. Despite its widespread use, a majority of GBM patients do not respond to TMZ therapy; expression of the O 6 -methylguanine DNA methyltransferase (MGMT) enzyme and loss of mismatch repair (MMR) function as the principal clinical modes of resistance to TMZ. Here, we describe a novel imidazotetrazine designed to evade resistance by MGMT while retaining suitable hydrolytic stability, allowing for effective prodrug activation and biodistribution. This dual-substituted compound, called CPZ, exhibits activity against cancer cells irrespective of MGMT expression and MMR status. CPZ has greater blood−brain barrier penetrance and comparable hematological toxicity relative to TMZ, while also matching its maximum tolerated dose in mice when dosed once-per-day over five days. The activity of CPZ is independent of the two principal mechanisms suppressing the effectiveness of TMZ, making it a promising new candidate for the treatment of GBM, especially those that are TMZ-resistant.
The blood−brain barrier (BBB) presents a major hurdle in the development of central nervous system (CNS) active therapeutics, and expression of the P-glycoprotein (P-gp) efflux transporter at the blood−brain interface further impedes BBB penetrance of most small molecules. Designing efflux liabilities out of compounds can be laborious, and there is currently no generalizable approach to directly transform periphery-limited agents to ones active in the CNS. Here, we describe a targetagnostic, prospective assessment of P-gp efflux using diverse compounds. Our results demonstrate that reducing the molecular size or appending a carboxylic acid in many cases enables evasion of P-gp efflux in cell-based experiments and in mice. These strategies were then applied to transform a periphery-limited V600E BRAF inhibitor, dabrafenib, into versions that possess potent and selective anti-cancer activity but now also evade P-gpmediated efflux. When compared to dabrafenib, the compound developed herein (everafenib) has superior BBB penetrance and superior efficacy in an intracranial mouse model of metastatic melanoma, suggesting it as a lead candidate for the treatment of melanoma metastases to the brain and gliomas with BRAF mutation. More generally, the results described herein suggest the actionability of the trends observed in these target-agnostic efflux studies and provide guidance for the conversion of non-BBBpenetrant drugs into versions that are BBB-penetrant and efficacious.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.