Biapenem

Tuberculosis (TB) still tops the list of global health burdens even after COVID-19. However, it will sooner transcend the current pandemic due to the prevailing risk of reactivation of latent TB in immunocompromised individuals. The indiscriminate misuse and overuse of antibiotics have resulted in the emergence of deadly drug-resistant variants of Mycobacterium tuberculosis (M.tb). This study aims to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM) in generating long-lasting immunity against TB. BPM treatment significantly boosted the activation status of the innate immune arm-macrophages by augmenting p38 signaling. Macrophages further primed and activated the adaptive immune cells CD4⁺ and CD8⁺ T-cells in the lung and spleen of the infected mice model. Furthermore, BPM treatment significantly amplified the polarization of T lymphocytes toward inflammatory subsets, such as Th1 and Th17. The treatment also helped generate a long-lived central memory T-cell subset. The generation of central memory T lymphocyte subset upon BPM treatment in the murine model led to a significant curtailing in the recurrence of TB due to reactivation and reinfection. These results suggest the potentiality of BPM as a potent adjunct immunomodulator to improve host defense against M.tb by enriching long-term protective memory cells. IMPORTANCE Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) tops the list of infectious killers around the globe. The emergence of drug-resistant variants of M.tb has been a major hindrance toward realizing the "END TB" goal. Drug resistance has amplified the global burden toward the quest for novel drug molecules targeting M.tb. Host-directed therapy (HDT) offers a lucrative alternative to tackle emerging drug resistance and disease relapse by strengthening the host's immunity. Through our present study, we have tried to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM). BPM treatment significantly augmented long-lasting immunity against TB by boosting the innate and adaptive immune arms. The generation of long-lived central memory T lymphocyte subset significantly improved the disease outcome and provided sterilizing immunity in the murine model of TB. The present investigation's encouraging results have helped us depict BPM as a potent adjunct immunomodulator for treating TB.

Objective: To evaluate the activity of six β-lactams in combination with three β-lactamase inhibitors against mycobacterium tuberculosis(MTB) in vitro. Methods: A total of 105 multidrug-resistant tuberculosis (MDR-TB) strains from different regions of Henan province from January to September 2020 were included in this study. Drug activity of six β-lactams (biapenem, meropenem, imipenem, doripenem, ertapenem and tebipenem) alone or in combination with β-lactamase inhibitors (clavulanic acid, avibactam and relebactam) was examined by minimum inhibitory concentration method (MICs) against 105 clinical isolates. Mutations of blaC, ldt_mt1 and ldt_mt2 were analyzed by PCR and DNA sequencing. Chi-square test was used to compare the antimicrobial activities of different β-lactam drugs. Results: Out of the β-lactams used herein, tebipenem was the most effective against MDR-TB and had an MIC₅₀ value of 8 mg/L(χ²=123.70,P=0.001). Besides, after the addition of β-lactamase inhibitors, the MICs of most β-lactam drugs were reduced more evidently in the presence of avibactam and relebactam compared to clavulanic acid.Especially, relebactam decreased both the MIC50 and MIC90 of telbipenem by 16-fold, and diluted the MIC of 23 (21.90%) and 41 (39.04%) isolatesby 32-fold and 16-fold.In addition, a total of 13.33% (14/105) of isolates harbored mutations in the blaC gene, with three different nucleotide substitutions: AGT333AGG, AAC638ACC and ATC786ATT. For the strains with Ser111Arg and Asn213Thr substitution in BlaC, the MIC values of the meropenem-clavulanate combination were reduced compared with a synonymous single nucleotide polymorphism (SNP) group. Conclusions: Both avibactam and relebactam had better synergistic effects on β-lactams than clavulanic acid. The combination of tebipenem and relebactam showed the most potent activity against MDR-TB isolates. In addition, the Ser111Arg and Asn213Thr substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem in the presence of clavulanate.