Review
Special Issue: Celebrating 30 years of biotechnology
Combination approaches to combat multidrug-resistant bacteria

https://doi.org/10.1016/j.tibtech.2012.12.006Get rights and content

The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic–antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants.

Highlights

► Combination approaches to combat multidrug-resistant bacteria. ► The problem of drug-resistant bacterial infections continues to worsen. ► Bacteria will inevitably acquire resistance against new antibiotics. ► Antibiotic–adjuvant combinations are an attractive approach to treat infections.

Section snippets

The problem of multidrug-resistant bacteria

The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria has become a significant global public health threat. Drug-resistant bacterial infections cause considerable patient mortality and morbidity, and rising antibiotic resistance is seriously threatening the vast medical advancements made possible by antibiotics over the past 70 years [1]. For example, in 2005 almost 95 000 people acquired methicillin-resistant Staphylococcus aureus (MRSA) infections in the United

Combinations of two or more antibiotics

One approach to combating MDR infections is combination of two or more antimicrobial drugs during a treatment regimen. Although the possibility of drug–drug interactions is a possible pitfall to this approach, and must be taken into consideration during the drug development process, combination therapy is common and critical in many areas of medicine. For example, drug combinations are key to most cancer treatments [9]. Combination therapy regimens have long been used to treat HIV-infected

Antibiotic/adjuvant combinations

An alternative to the combination of two or more drugs with known antibiotic activity for the treatment of MDR bacterial infections is to combine an antibiotic with a compound that is not, when administered alone, microbicidal but increases the activity of the antibiotic, for example, by blocking the mechanism of resistance to the antibiotic. Such an approach is particularly attractive because it may also result in a decrease in the onset of resistance development. Antibiotic resistance

Screening of previously approved drugs

The redeployment of drugs that have previously been approved for other indications is an attractive approach to the discovery of antibiotic adjuvants because these drugs have known toxicology and pharmacology profiles. It is estimated that by taking this approach, the overall cost of bringing a drug to market can be reduced by almost 40%, as a result of elimination of much of the toxicological and pharmacokinetic assessment required for drug approval [48]. Systematic screening of approved

Concluding remarks

With the continuing rise in occurrence of drug-resistant strains of bacteria, new approaches to combating infections caused by these bacteria are urgently needed, particularly for Gram-negative bacteria. The one drug–one target model has limited viability, and combination therapy is the norm in the treatment of many cancers, viral infections such as HIV, and tuberculosis. The use of combination therapy, or other drug cocktails such as antibiotic/adjuvant combinations for the treatment of other

Acknowledgments

We would like to thank the NIH (R01GM055769 and R21AI096015), the V foundation, and the DOD DMRDP program (W81XWH-11-2-0115) for their support. The DMRDP program is administered by the Department of Army; the US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering office. The content of this manuscript does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.

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