Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, a novel semisynthetic series of spectinomycin analogs was generated with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross-resistance with existing tuberculosis therapeutics, activity against MDR/XDR-tuberculosis, and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target based tuberculosis drug discovery.

Two mechanisms are thought to be involved in the natural drug resistance of mycobacteria: the mycobacterial cell wall permeability barrier and active multidrug efflux pumps. Genes encoding drug efflux transporters have been isolated from several mycobacterial species. These proteins transport tetracycline, fluoroquinolones, aminoglycosides and other compounds. Recent reports have suggested that efflux pumps may also be involved in transporting isoniazid, one of the main drugs used to treat tuberculosis. This review highlights recent advances in our understanding of efflux-mediated drug resistance in mycobacteria, including the distribution of efflux systems in these organisms, their substrate profiles and their contribution to drug resistance. The balance between the drug transport into the cell and drug efflux is not yet clearly understood, and further studies are required in mycobacteria.

Tuberculosis is one of the major causes of infection across the world. The emergence of multi-, extensively- and totally drug-resistant strains of Mycobacterium tuberculosis contributes to the lack of therapeutic options available. The mechanisms associated with this resistance could involve mutations in genes coding for target proteins, decreased permeability, increased efflux and so on. Resistance mediated by efflux systems has become more relevant, since these systems help the bacteria to extrude antibiotics until relevant mutations emerge and become established in the population. Therefore, compounds that inhibit these transport systems are of major importance and have been studied in the last few years. Not only do these compounds act on the bacterial efflux systems but they have also been explored for their dual role as boosters of the macrophage-infected cells. The search for novel compounds or combinations of adjuvant compounds and antibiotics to treat mycobacterial multidrug-resistant infections has become a major goal in the treatment of these diseases.

SummarywhiI is one of several loci originally described as essential for sporulation in Streptomyces coelicolor A3(2). We have characterized whiI at the molecular level. It encodes an atypical member of the response regulator family of proteins, lacking at least two of the residues strongly conserved in the conventional phosphorylation pocket. It is not adjacent to a potential sensor kinase gene. Fifteen mutant alleles of whiI were sequenced, revealing, among others, six mutations affecting conserved amino acids, several frameshift mutations and one mutation in the promoter. The whiI promoter is speci®cally transcribed by the sporulation-speci®c s WhiG -containing form of RNA polymerase. Transcription of whiI is temporally controlled, reaching a maximum level coincident with the formation of spores. Further transcriptional studies suggested that WhiI is involved directly or indirectly in repressing its own expression and that of another s WhiG -dependent sporulation-speci®c regulatory gene, whiH.