In Vitro Activity of a Novel Siderophore-Cephalosporin, GT-1 and Serine-Type β-Lactamase Inhibitor, GT-055, against Escherichia coli, Klebsiella pneumoniae and Acinetobacter spp. Panel Strains

Abstract

This study investigates GT-1 (also known as LCB10-0200), a novel-siderophore cephalosporin, inhibited multidrug-resistant (MDR) Gram-negative pathogen, via a Trojan horse strategy exploiting iron-uptake systems. We investigated GT-1 activity and the role of siderophore uptake systems, and the combination of GT-1 and a non-β-lactam β-lactamase inhibitor (BLI) of diazabicyclooctane, GT-055, (also referred to as LCB18-055) against molecularly characterised resistant Escherichia coli, Klebsiella pneumoniae and Acinetobacter spp. isolates. GT-1 and GT-1/GT-055 were tested in vitro against comparators among three different characterised panel strain sets. Bacterial resistome and siderophore uptake systems were characterised to elucidate the genetic basis for GT-1 minimum inhibitory concentrations (MICs). GT-1 exhibited in vitro activity (≤2 μg/mL MICs) against many MDR isolates, including extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing E. coli and K. pneumoniae and oxacillinase (OXA)-producing Acinetobacter spp. GT-1 also inhibited strains with mutated siderophore transporters and porins. Although BLI GT-055 exhibited intrinsic activity (MIC 2–8 μg/mL) against most E. coli and K. pneumoniae isolates, GT-055 enhanced the activity of GT-1 against many GT-1–resistant strains. Compared with CAZ-AVI, GT-1/GT-055 exhibited lower MICs against E. coli and K. pneumoniae isolates. GT-1 demonstrated potent in vitro activity against clinical panel strains of E. coli, K. pneumoniae and Acinetobacter spp. GT-055 enhanced the in vitro activity of GT-1 against many GT-1–resistant strains.

In Vitro Activity of a Novel Siderophore-Cephalosporin LCB10-0200 (GT-1), and LCB10-0200/Avibactam, against Carbapenem-Resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa Strains at a Tertiary Hospital in Korea

“…Against KPC- producing strains, LCB10-0200 had a high activity with the MIC range of ≤0.12–16 mg/L, and a MIC 50 of 1 mg/L. The MIC 90 in KPC- producing strains was also 8 mg/L, being similar with the previous report [ 11 ]. LCB10-0200 activity was significantly enhanced in combination with AVI, (i.e., LCB10-0200/AVI MIC 90 was at least 16-fold lower than CAZ-AVI MIC 90 ).…”

“…Secondly, novel approaches including inhaled delivery and liposomal delivery have been developed to increase antibiotic concentration in lung infection and to overcome the low drug permeability [ 41 , 42 ]. One way to improve the drug influx into the bacterial membrane is the conjugation between antibiotic and siderophore, a.k.a “Trojan horse” strategy, which was applied in the development of LCB10-0200 [ 11 ]. Importantly, recent advances in bioinformatics, machine learning, and deep learning have been applied in prediction of antimicrobial molecules [ 43 , 44 ].…”

“…It was well-described in the literature that one of the most common carbapenem resistance mechanisms in A. baumannii and P. aeruginosa is possession of OXA-23 and other OXA-type carbapenemases [ 49 , 50 , 51 , 52 ]. In our previous study, the in vitro activity of LCB10-0200 against the classified panel strains showing diverse carbapenem susceptibility was measured [ 11 ]. For example, in A. baumannii panel strains, there were 11 isolates including narrow-spectrum oxacillinase (one isolate), ESBL-AmpC beta-lactamase (three isolates), ESBL-AmpC beta-lactamase (two strains), ESBL-AmpC-carbapenemase-producing strains (five strains).…”

“…In a previous study, our group evaluated the in vitro activity of LCB10-0200 against panels of well-characterised E. coli , K. pneumoniae , and Acinetobacter spp. strains showing diverse antibiograms [ 11 , 12 , 13 ]. Panel strains of these three species were classified into different groups, including Non-Extended Spectrum β-lactamase (Non-ESBL), ESBL-, ESBL-AmpC-, AmpC-carbapenemase- and ESBL-carbapenemase-producing strains.…”

Emerging Strategies to Combat β-Lactamase Producing ESKAPE Pathogens

“…Other BLIs were introduced for the next generation of combined therapy, one such class of newer, non-β-lactam BLIs is represented by the diazabicyclooctanes (DABCOs), based on a (5R)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulphate core, of which the approved compounds for clinical use are: avibactam, relebactam, macubactam, zidebactam, and nacubactam (active against MDR Gram-negative rods) and are able to augment the activity of β-lactams in the absence of β-lactamases [ 141 ] in a different species including A. baumannii [ 142 ] and P. aeruginosa [ 131 ]; WCK 5107, WCK 5153 (a β-lactam enhancer effect against A. baumannii [ 142 ] and P. aeruginosa strains [ 131 ]); WCK 4234 and his combination with meropenem called WCK 5999, has been shown to be superior to meropenem monotherapy against MDR clinical isolates of A. baumannii [ 143 ], including OXA-23- and OXA-24-producing strains, K. pneumoniae [ 144 ], and P. aeruginosa [ 143 ]; ETX2514 (a DABCO analogue with class A, C, and broad class D β-lactamase inhibitory activity) [ 132 ]; active especially against the class D enzymes OXA-10, OXA-23 and OXA-24 [ 132 ], Enterobacteriaceae including mcr-1- positive E. coli , E. cloacae , Stenotrophomonas maltophilia , Citrobacter spp. and class B β-lactamase-positive and -negative CRE); GT-055 (active against class A, C, D, and some class B β-lactamases, has intrinsic activity against some Enterobacteriaceae and is reported to potentiate GT-1 against MDR strains of A. baumannii and P. aeruginosa strains) [ 145 ]; boronic acid transition state inhibitors (BATSIs) a BLI with activity against serine β-lactamases and of the BATSIs—vaborbactam.…”