Polio-like motor paralysis associated with acute hemorrhagic conjunctivitis in an outbreak in 1981 in Bombay, India: clinical and serologic studies

High and rising neutralizing antibody titers (NATs) to enterovirus type 70 (EV70) were detected in the serum and cerebrospinal fluid (CSF) of patients with polio-like motor paralysis accompanying acute hemorrhagic conjunctivitis (AHC) in an outbreak of AHC in 1981 in Bombay, India. Fifty-four (88.5%) of 61 patients with AHC with or without neurologic disease had serum NATs of ≥ 1:16, and some paired sera from these patients showed significant increases in NAT. Serum from noninfected control subjects had no significant neutralizing antibody to EV70. Thirty-six (94.7%) of 38 CSF specimens from 30 patients with spinal or a combination of spinal and cranial motor paralysis associated with AHC had NATs ranging from 1:2 to 1:256. No neutralizing antibody was found in CSF specimens from patients with AHC alone or in those from non-infected control subjects, and a reduced ratio of serum NAT to CSF NAT was detected in patients with neurologic disease. Therefore, it is highly likely that intrathecal synthesis of antibody occurred in response to direct invasion of the central nervous system by EV70. The results represent strong laboratory evidence of the neurovirulence of EV70

Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY

The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria. MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials