Antibiotic Adjuvants: Rescuing Antibiotics from Resistance

Resistance has emerged to all clinically used antibiotics. It is a global health care crisis that is one of the major challenges to health care in the 21st century. There is a growing gap between the clinical need for new antibiotics and new drug discovery and development. It is increasingly challenging to find new antibiotics and to bring them to market. Preserving our existing antibiotics offers a way to mitigate the gap between the need for new drugs and the diminishing supply pipeline. This can be accomplished in several ways, including the development of antibiotic adjuvants. Antibiotic adjuvants are nonantibiotic compounds that enhance antibiotic activity either by blocking resistance or by boosting the host response to infection. Several are already in clinical use, specifically compounds that inhibit the β-lactamases that confer resistance to β-lactam antibiotics. Rooted in the mechanism of action of antibiotics and subject to bacterial evolution, antibiotic resistance is difficult and perhaps impossible to overcome. Nevertheless, strategies can be used to minimize the emergence and impact of resistance. Antibiotic adjuvants offer one such approach. These are compounds that have little or no antibiotic activity themselves but act to block resistance or otherwise enhance antibiotic action. Antibiotic adjuvants are therefore delivered in combination with antibiotics and can be divided into two groups: Class I agents that act on the pathogen, and Class II agents that act on the host. Adjuvants offer a means to both suppress the emergence of resistance and rescue the activity of existing drugs, offering an orthogonal strategy complimentary to new antibiotic discovery Video Abstract eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI1NjllMTZhYTNjYzllYzU2NzUxM2U4ZDM0YWI0MGEyZiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NjM2MjkyfQ.prcA0vAWMIvrSfho-pJ10V_Qzj0aE8ZOQ36sGr8QKICD4py9LIjpO3MXLSmx-nQMEScoQvmmLxG9FSQdO72NdU6JeT9w5FFtB4y7DJS-Xz7Edi9syj6lKGadeLouTvD2zFyla5JhmTyegn74X2BALS7SrkUE0_Yo8RS-xTSEXW7AnjgAQBe1A361sUXUSkaUFPmvoWCWsjcon0-JLiCecOtdCwjrICNyOL_spdgvhuyVhHNTKFzxNpwHp5NRZ3wps4C-wGETQMGyfMT1ral6dQvHdyRxhxAHnkFFDPkasiPf79CzfCrUaBM8VDw5s_ntpii55OsHA2JCBAG4mhn0EQ (mp4, (73.26 MB) Download video Rooted in the mechanism of action of antibiotics and subject to bacterial evolution, antibiotic resistance is difficult and perhaps impossible to overcome. Nevertheless, strategies can be used to minimize the emergence and impact of resistance. Antibiotic adjuvants offer one such approach. These are compounds that have little or no antibiotic activity themselves but act to block resistance or otherwise enhance antibiotic action. Antibiotic adjuvants are therefore delivered in combination with antibiotics and can be divided into two groups: Class I agents that act on the pathogen, and Class II agents that act on the host. Adjuvants offer a means to both suppress the emergence of resistance and rescue the activity of existing drugs, offering an orthogonal strategy complimentary to new antibiotic discovery nonantibiotic molecule that potentiates the activity of an antibiotic. compounds that block antibiotic resistance. Class I.A adjuvants block active resistance, that is, specific inactivating enzymes, bypass mechanisms etc., Class I.B adjuvants overcome metabolic or physiologic barriers to antibiotic activity, e.g., facilitate membrane penetration, block biofilms, etc. compounds that enhance antibiotic action by interacting with host defense mechanisms. proteins and protein complexes that actively (i.e., use energy) move antibiotics out of the cell against a concentration gradient. Antibiotic Adjuvants: Rescuing Antibiotics from Resistance: (Trends in Microbiology , 862–871; October 17, 2016)Gerard D. WrightTrends in MicrobiologyAugust 10, 2016In BriefErrors in the structures avibactam and relebactam in Figure 3 have been corrected. Full-Text PDF