Deciphering unexploited features of drug-repurposing beta-lactams against tuberculosis : from genomic patterns of Mycobacterium tuberculosis susceptibility to synergistic combinations

• Main Author: Olivença, Francisco
• Publication Date: 2023
• Language: eng
• Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Download full: http://hdl.handle.net/10400.5/98221
• topic: tuberculose; Mycobacterium tuberculosis; resistência antimicrobiana; antibióticos beta-lactâmicos; reposicionamento de fármacos; tuberculosis; antimicrobial resistance; beta-lactam antibiotics; drug-repurposing; Domínio/Área Científica::Ciências Naturais::Ciências Biológicas

Tuberculosis (TB) still figures as one of the leading death causes by a single infectious agent worldwide. The natural capacity of Mycobacterium tuberculosis (Mtb) to evade and subvert host immune responses, coupled with the increasing threat of drug-resistant TB (DR-TB), contribute to the difficult containment of this infection. Alternative treatment options for DR-TB are desperately required, either by identification of novel antimicrobials or by repurposing existing drugs. Through an approach focused on the essential nature of the peptidoglycan, a core layer of the cell wall, this work aims to reevaluate presumed paradigms behind the historically restricted use of beta-lactams in TB and to unveil new dimensions of the effects of this class against the causative agent. The results of a large-scale beta-lactam susceptibility screening in clinical Mtb isolates corroborate previous observations, with the majority of the strains displaying low minimum inhibitory concentrations to carbapenems combined with clavulanate. Furthermore, correlation of these results with whole-genome sequencing data allowed us to show that drug-resistant strains of one of the main sublineages circulating in Portugal were more susceptible to beta-lactams. Acquired mycobacterial resistance to inhibitors of peptidoglycan synthesis was addressed in parallel in the reference strains Mtb H37Rv and Mycolicibacterium smegmatis mc2 -155. Beta-lactamase or peptidoglycan transpeptidase genes were mostly conserved and mutations arose in genes encoding lesser-known lipoproteins with predicted penicillin-binding activity or transcription regulators. The extracellular and intracellular interactions between beta-lactams and conventional antimycobacterials were also explored, revealing a promising synergistic effect between meropenem/clavulanate and the first-line antibiotic ethambutol. In addition to the antimicrobial effect, subsequent experiments indicated that this combination may also impair the concealment of the peptidoglycan to a greater extent than the individual antibiotics, potentially threatening pathogen evasion and survival. This comprehensive study supports the activity of specific beta-lactams against Mtb. The outputs contribute to an integrated understanding of the rational application of this well-characterized class in TB, in alignment with the WHO END TB goals of maximizing favorable clinical outcomes and suppressing disease burden.