The below list represents only planned manuscripts. Some of these
manuscripts have not been received by the Editorial Office yet. Papers
submitted to MDPI journals are subject to peer-review.
Type of the Paper: Review
Title: Mechanisms involved in resistance to antimicrobial peptides produced by Gram-positive bacteria
Authors: Maria do Carmo de Freire Bastos1* and Marcus Lívio Varella Coelho1,2
Affiliations: Departmento de Microbiologia Geral1, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, and Instituto Nacional da Propriedade Industrial2, INPI, Rio de Janeiro, Brasil
Abstract: Bacteriocins are antimicrobial peptides or proteins which are produced by a large variety of bacteria. They typically inhibit the growth of strains closely related to the producer strain although many bacteriocins are able to inhibit different species of bacteria. Most bacteriocins are bactericidal to the target micro-organism. In Gram-positive bacteria, they are currently classified into four major classes. Class I bacteriocins, or lantibiotics, are small, heat-stable peptides characterized by the presence of post-translationally modified amino acids. Class II bacteriocins are small, heat-stable peptides which do not contain modified amino acids. Class III bacteriocins are heat-labile antimicrobial proteins. Finally, class IV bacteriocins are cyclic peptides, with a posttranslational covalent linkage between the carboxy and amino termini. Interest in bacteriocins has increased recently due to their antimicrobial activity especially towards Gram-positive pathogens. These substances have potential biotechnological applications in either food preservation or prevention and control of bacterial infections which affect humans and animals. However, there is concern that prolonged exposure to bacteriocins may give rise to cells resistant to them, as observed for conventional antibiotics. Therefore, in the present review, we will attempt to provide the reader with an overview of the prevalence, development, and molecular mechanisms involved in resistance to bacteriocins produced by Gram-positive bacteria. We will also discuss strategies that can be used to overcome this resistance.
Title: Mechanisms of glycopeptide-resistance in the producing actinomycetes
Authors: Binda E1,2, Marinelli F 1,2 and Marcone GL1,2
1Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
2 The Protein Factory, Interuniversity Centre Politecnico di Milano, ICRM CNR Milano and University of Insubria, Milan, Italy
Abstract: Glycopeptides are considered antibiotics of last resort for the treatment of life-threatening infections caused by important multi-resistant Gram-positive human pathogens such as Staphylococcus aureus, Enterococcus spp. and Clostridium difficile. The emergence of glycopeptide-resistant clinical isolates first among enterococci and then in staphylococci has prompted the research for second generation-glycopeptides and a flurry of activity aimed at understanding resistance mechanisms and their evolution. Glycopeptides are glycosylated non-ribosomal peptides produced by a diverse group of soil actinomycetes. They target Gram-positive bacteria by binding to the acyl-D-alanyl-D-alanine (D-Ala-D-Ala) terminus of the growing peptidoglycan on the outer surface of cytoplasmatic membrane. Glycopeptide-resistant organisms avoid such a fate by replacing D-Ala-D-Ala terminus with D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine (D-Ala-D-Ser), thus markedly reducing antibiotic affinity for its cellular target. Resistance has manifested itself largely through the expression of genes (named van) encoding proteins that reprogram cell wall biosynthesis and thus evade the action of the antibiotic. These resistance mechanisms were most likely co-opted from the glycopeptide producing actinomycetes - which use them to avoid suicide during antibiotic production - rather than being orchestrated by pathogen bacteria upon continued treatment. van-like gene clusters, similar to those described in enterococci, were in fact identified in many glycopeptide-producing actinomycetes like Actinoplanes teichomyceticus producer of teicoplanin and Streptomyces toyocaensis which produces the A47934 glycopeptide. Interestingly in these microbes the genes devoted to antibiotic production and to self-resistance are clustered within the genome and their expression is co-regulated by the same environmental signals. In this paper, we review the recent discoveries on the strategies of self-resistance mechanisms used by the actinomycetes, with a particular attention to those recently described in Nonomuraea sp. ATCC 39727. Nonomuraea sp. ATCC 39727 is the producer of A40926 that is the natural precursor of the second-generation semisynthetic glycopeptide dalbavancin, currently completing Phase III of clinical trials. A thorough understanding of glycopeptide self-resistance mechanisms in the producing microorganisms may be particularly relevant to predict and eventually control the evolution of resistance that might arise following the introduction in clinics of dalbavancin and other second-generation glycopeptides. Moreover, it may reveal new understanding of the molecular mechanisms linking antibiotic production to self-resistance, thus enabling knowledge-based approaches to strain improvement and facilitating drug production processes.
Type of Paper: Review
Title: Drug resistance mechanisms in Mycobacterium tuberculosis
Authors: Juan Carlos Palomino and Anandi Martin
Abstract: Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been reported. A better knowledge on the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis.
Type of Paper: Article, Review, Communication
Title: b-Lactam Antibiotics Renaissance
Authors: Qin Wenling1, Mauro Panunzio *1 and Stefano Biondi 2,*
Affiliations: 1 ISOF-CNR Dipartimento di Chimica “G. Ciamician” Via Selmi, 2 40126 Bologna, (Italy)
2 Allecra Therapeutics SAS / 13 rue du Village Neuf, 68300, Saint Louis, (France)
Abstract: Treatment of bacterial infections by b-lactam antibiotics have been successfully used for many years. However, the emergence and dissemination of resistance has reached the point where many of the marketed b-lactams are no longer clinically effective. The increasing incidence of multidrug-resistant bacteria and the progressive withdrawal of pharmaceutical companies from antibiotic research has stimulated a strong reaction from health authorities who have put in place initiatives to stimulate the discovery of new antibacterials. Despite this gloomy scenario, a number of novel b-lactam antibiotics as well as b-lactamase inhibitors have been recently progressed into clinical trials, and many more such compounds are being investigated. In this review we seek to provide highlights of recent developments in the discovery of novel b-lactam antibiotics and b-lactamase inhibitors
Keywords: b-lactam antibiotics; b-lactamase inhibitors; bacterial infections