It has been over 40 years since new approach to treating Gram-negatives was approved. It is predominantly the physiology of Gram-negative bacterium, specifically the make-up of the outer-membrane of these bacteria that has hindered innovation. Whilst Gram-positive bacteria possess a single phospholipid cell membrane, Gram-negative bacteria have both a phospholipid inner membrane (akin to the Gram-positive membrane) and an outer membrane bilayer composed primarily of phospholipid at the inner surface and lipopolysaccharide (LPS) at the outer leaflet. It is this layer of highly polar, negatively charged LPS that excludes many excellent target-based inhibitors including to a trove of wonderful, clinically useful Gram-positive antibiotics from entering Gram-negative bacteria to do their work. Unfortunately, a distinct incongruence between chemical properties required for Gram-negative penetration (both membranes) and that imposed by many of the known (and novel) bacterial targets means that simple (or complex) medicinal chemistry tactics have not been able to provide a solution.
Spero Therapeutics believes its adjunctive, Potentiator approach (SPR741 & SPR206) to LPS disruption will be the solution.
SPR741: SPR741 is an IV product; however, it does not have any significant antimicrobial activity on its own. SPR741 when combined with an antibiotic has demonstrated the ability to expand and increase the spectrum against Gram-negative bacteria, including organisms identified by CDC and WHO as urgent and serious threats. SPR741 has demonstrated ability to expand the spectrum and enhance the potency of over two dozen existing antibiotics and enable expanded utility against Gram-negative pathogens. SPR741 is currently in Phase 1 trials.
SPR206: Our next generation Potentiator molecule is an IV direct-acting antibiotic that exhibits extremely high potency against multi-drug resistant pathogens that cause mortality, including Acinetobacter baumanii and Pseudomonas aeruginosa. SPR206 is currently in IND-enabling studies.