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This situation has been reached due to (i) the inappropriate and excessive use of antibiotics in medicine, the veterinary field and agriculture over the years, with these drugs even used for the treatment of nonbacterial infections (ii) a severe investment gap in R&D by the pharmaceutical industry after the 1990s because antibiotics are not profitable enough and (iii) the lack of innovative strategies for the development of new antibiotics. (11) Infections from resistant bacteria are now too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or even no treatments are available.
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Although bacterial resistance to antibiotics is an inevitable natural phenomenon because of the great adaptability and the intrinsic evolutionary character of bacteria, human behavior is one of the main factors responsible for converting this natural behavior into one of the gravest public health issues of the early 21st century. We are in danger of entering an era in which antibiotics are no longer available to treat infections in clinical settings, including the common infectious complications in vulnerable patients who are receiving cancer chemotherapy, organ transplants, dialysis for kidney failure, and general surgery for which the ability to treat secondary infections is crucial.
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(1−10) These microorganisms have the innate ability to find new ways to resist treatment and are able to transmit genetic material to other bacteria, which can in turn become drug-resistant. Unfortunately, the ability of these drugs to cure bacterial infections is now at serious risk due to the emergence and worldwide spread of superbugs (multiresistant bacteria). The discovery of antibiotics has managed to cure diseases that were fatal in the past, thus contributing to increased life expectancy. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. This Perspective is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-negative bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems, and monobactams), by the production of β-lactamases. Three main types of compounds have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors (ii) outer membrane permeabilizers (iii) efflux pump inhibitors. These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clinical use.
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In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy “antibiotic + inhibitor of resistance”. Infections caused by resistant bacteria are nowadays too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or even no treatments are available.