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Alternative therapeutics against MDR bacteria – “fighting the epidemic of antibiotic resistance”

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The ongoing emergence and spread of multidrug resistant (MDR) bacteria is a major public health issue. The fact that the antibiotic discovery pipeline is empty has contributed to the emergence of untreatable infections, such as gonorrhea, pneumonia, extensively-drug resistant tuberculosis, among others. ...

The ongoing emergence and spread of multidrug resistant (MDR) bacteria is a major public health issue. The fact that the antibiotic discovery pipeline is empty has contributed to the emergence of untreatable infections, such as gonorrhea, pneumonia, extensively-drug resistant tuberculosis, among others. During the past 10 years, infections caused by MDR Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. Reported rates of infection attributed to these bacteria continue to increase, and are no longer limited to those associated severely ill, immuno-compromised or elderly patients within the healthcare systems. Community-acquired infections are rapidly on the rise contributing to the ever-increasing burden of these MDR-associated infections. Unless we can develop novel strategies to reverse this antibiotic resistance, we can expect to see a substantial rise in incurable infections and fatalities in both developed and developing countries.

Antibiotic resistance can develop through complex interactions, with resistance arising by de-novo mutation under clinical antibiotic selection or frequently through the acquisition of mobile genetic elements (plasmids, integrative conjugative elements, prophages, transposons, etc.). A lot of focus has been on the role of mutations in specific genes, for example the quinolone resistance-determining regions (QRDR), and specific antibiotic-modifying enzymes, such as extended-spectrum beta-lactamases. However, reductions in the permeability of the bacterial cell envelope through the reduced expression of porins, the over-expression of efflux pumps and alterations in the structure of lipopolysaccharide (LPS) plays a significant role in resistance by preventing the antibiotics from penetrating the bacterial cell wall. All of these factors have contributed to the lack of new molecules discovered in the last number of years. New efforts have focused on more specific bacterial targets, screening large libraries of synthetic compounds, but even that approach has proven unsuccessful so far.

Alternative approaches using new or old compounds are therefore urgently needed. One such example is the so-called combination therapy, combining “old” antibiotics and other compounds (such as efflux pump inhibitors) to enhance the activity of the antibiotic. Combined antibiotic therapy for invasive infections with Gram-negative bacteria is already being employed in many health care facilities, especially for particular subgroups of patients, such as those with neutropenia; infections caused by Pseudomonas aeruginosa; ventilator-associated pneumonia, or patients that are severely ill. Given the therapeutic potential of efflux pump inhibition, further studies exploring novel strategies to interfere with efflux pump expression and functions are necessary. This includes rational design of efflux pump inhibitors using information of the pumps structure and well-defined bacterial models. In addition, the use of non-traditional approaches such as pump inhibition by gene silencing, antibodies and perhaps even phage are to be of interest. The use of probiotics, essential oils, compounds extracted from plants, bacterial preparations, peptides and nanoparticles are also being investigated. These so-called alternative strategies will be the focus of discussion in this topic.


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