Abstract
ABSTRACTThe infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria.
Highlights
The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind
Our data demonstrate that (i) LpxC is a valid drug target for the treatment of common Gram-negative bacterial infections caused by MDR/XDR strains and (ii) LPC-069 is the first therapeutically attractive compound in a new class of antibiotics with activity against LpxC
LPC-058’s antibacterial activity fell by a factor of 32 and 64 when Y. pestis was cultured at 28°C and 37°C, respectively, in the presence of 2% serum albumin; this probably reflects a high level of plasma protein binding and low tissue penetration (Fig. 1)
Summary
The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. The data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrugresistant and extensively drug-resistant carbapenemase-producing strains. Our previous in vitro investigation highlighted the therapeutic potential of LpxC inhibitors against MDR and extensively drug-resistant (XDR) Gram-negative bacilli in general and carbapenemase-producing strains in particular [11]. Previous investigations used animal models of prophylactic treatment (i.e., treatment initiated Յ60 min postchallenge) and did not assess the treatment of infections caused by highly aggressive pathogens such as Yersinia pestis These limitations have profound implications for the use of LpxC inhibitors as real-world therapeutics; extremely potent LpxC inhibitors may be able to maintain high levels of host viability during treatment, they may fail to cure the disease if they cannot completely clear the bacterial load
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