Resurrecting Old β-Lactams: Potent Inhibitory Activity of Temocillin against Multidrug-Resistant Burkholderia Species Isolates from the United States

• Published in: Antimicrobial agents and chemotherapy 2019-04, Vol.63 (4)
• Main Authors: Zeiser, Elise T, Becka, Scott A, Barnes, Melissa D, Taracila, Magdalena A, LiPuma, John J, Papp-Wallace, Krisztina M
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; beta-Lactamases - metabolism; beta-Lactams; beta-Lactams - pharmacology; Burkholderia; Burkholderia - drug effects; Burkholderia - metabolism; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - drug effects; Humans; Mechanisms of Resistance; Microbial Sensitivity Tests - methods; Penicillins; Penicillins - pharmacology; Ticarcillin - pharmacology; United States
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02315-18

spp. are opportunistic human pathogens that infect persons with cystic fibrosis and the immunocompromised. spp. express class A and C β-lactamases, which are transcriptionally regulated by PenR through linkage to cell wall metabolism and β-lactam exposure. The potency of temocillin, a 6-methoxy-β-lactam, was tested against a panel of multidrug-resistant (MDR) spp. In addition, the mechanistic basis of temocillin activity was assessed and compared to that of ticarcillin. Susceptibility testing with temocillin and ticarcillin was conducted, as was biochemical analysis of the PenA1 class A β-lactamase and AmpC1 class C β-lactamase. Molecular dynamics simulations (MDS) were performed using PenA1 with temocillin and ticarcillin. The majority (86.7%) of 150 MDR strains were susceptible to temocillin, while only 4% of the strains were susceptible to ticarcillin. Neither temocillin nor ticarcillin induced expression. Ticarcillin was hydrolyzed by PenA1 ( / = 1.7 ± 0.2 μM s ), while temocillin was slow to form a favorable complex (apparent [ ] = ∼2 mM). Ticarcillin and temocillin were both potent inhibitors of AmpC1, with values of 4.9 ± 1.0 μM and 4.3 ± 0.4 μM, respectively. MDS of PenA revealed that ticarcillin is in an advantageous position for acylation and deacylation. Conversely, with temocillin, active-site residues K73 and S130 are rotated and the catalytic water molecule is displaced, thereby slowing acylation and allowing the 6-methoxy of temocillin to block deacylation. Temocillin is a β-lactam with potent activity against spp., as it does not induce expression and is poorly hydrolyzed by endogenous β-lactamases.